β2-adrenoceptor agonists

ABSTRACT

Compounds of formula 
                         
in free or salt or solvate form, where
     Ar is a group of formula   
     
       
         
         
             
             
         
       
         
         Y is carbon or nitrogen and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, n, p, q and r are as defined in the specification, their preparation and their use as pharmaceuticals, particularly for the treatment of obstructive or inflammatory airways diseases.

This is a divisional of application Ser. No. 10/009,008 filed on Jan. 8,2002, which is National Stage of International Application No.PCT/EP00/05058 filed on Jun. 2, 2000, the entire disclosures of whichare hereby incorporated by reference.

This invention relates to organic compounds, their preparation and theiruse as pharmaceuticals.

The invention provides in one aspect a compound of formula

in free or salt or solvate form, where

-   Ar is a group of formula

-   R¹ is hydrogen, hydroxy, or alkoxy,-   R² and R³ are each independently hydrogen or alkyl,-   R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, cyano,    hydroxy, alkoxy, aryl, alkyl, alkyl substituted by one or more    halogen atoms or one or more hydroxy or alkoxy groups, alkyl    interrupted by one or more hetero atoms, alkenyl, trialkylsilyl,    carboxy, alkoxycarbonyl, or —CONR¹¹R¹² where R¹¹ and R¹² are each    independently hydrogen or alkyl, or R⁴ and R⁵, R⁵ and R⁶, or R⁶ and    R⁷ together with the carbon atoms to which they are attached denote    a carbocyclic or heterocyclic ring,-   R⁸ is halogen, —OR¹³, —CH₂OR¹³ or —NHR¹³ where R¹³ is hydrogen,    alkyl, alkyl interrupted by one or more hetero atoms, —COR¹⁴, where    R¹⁴ is hydrogen, —N(R¹⁵)R¹⁶, alkyl or alkyl interrupted by one or    more hetero atoms, or aryl and R¹⁵ and R¹⁶ are each independently    hydrogen, alkyl or alkyl interrupted by one or more hetero atoms, or    R¹³ is —C(═NH)R¹⁷, —SOR¹⁷ or —SO₂R¹⁷ where R¹⁷ is alkyl or alkyl    interrupted by one or more hetero atoms, and-   R⁹ is hydrogen, or R⁸ is —NHR¹⁸ where —NHR¹⁸ and R⁹, together with    the carbon atoms to which they are attached, denote a 5- or    6-membered heterocycle,-   R¹⁰ is —OR¹⁹ or —NHR¹⁹ where R¹⁹ is hydrogen, alkyl, alkyl    interrupted by one or more hetero atoms, or —COR²⁰, where R²⁰ is    —N(R²¹)R²², alkyl or alkyl interrupted by one or more hetero atoms,    or aryl, and R²¹ and R²² are each independently hydrogen, alkyl or    alkyl interrupted by one or more hetero atoms,-   X is halogen or halomethyl or alkyl,-   Y is carbon or nitrogen,-   n is 1 or 2,-   p is zero when Y is nitrogen or 1 when Y is carbon,-   q and r are each zero or 1, the sum of q+r is 1 or 2; and-   the carbon atom marked with an asterisk * has the R or S    configuration, or a mixture thereof, when R¹ is hydroxy or alkoxy.

Terms used in this specification have the following meanings:

“Alkyl” denotes straight chain or branched alkyl, which may be, forexample, C₁ to C₁₀ alkyl such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl,straight or branched hexyl, straight or branched heptyl, straight orbranched nonyl or straight or branched decyl. Preferably alkyl is C₁ toC₄ alkyl. Alkyl substituted by one or more halogen atoms or one or morehydroxy or alkoxy groups may be any of the above C₁ to C₁₀ alkyl groupssubstituted by one or more halogen, preferably fluorine or chlorine,atoms, by one or more hydroxy groups or by one or more C₁ to C₁₀,preferably C₁ to C₄, alkoxy groups.

“Alkyl interrupted by one or more hetero atoms” denotes straight chainor branched alkyl e.g. C₂ to C₁₀ alkyl, in which one or more pairs ofcarbon atoms are linked by —O—, —NR—, —S—, —S(═O)— or —SO₂—, where R ishydrogen or C₁ to C₁₀ (preferably C₁ to C₄)alkyl. Preferred such groupsare alkoxyalkyl groups, preferably C₁-C₄-alkoxy-C₁-C₄-alkyl groups.

“Alkoxy” denotes straight chain or branched alkoxy and may be, forexample, C₁ to C₁₀ alkoxy such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or straight orbranched pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.Preferably alkoxy is C₁ to C₄ alkoxy.

“Alkenyl” means straight chain or branched alkenyl, which may beunsubstituted or substituted, for example by one or more halogen atomsor one or more alkoxy groups, and which may be, for example, C₂ to C₁₀alkenyl such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, orstraight or branched pentenyl, hexenyl, heptenyl, octenyl, nonenyl ordecenyl. Preferred alkenyl is C₂ to C₄ alkenyl.

“Aryl” denotes unsubstituted or substituted aryl, e.g. unsubstitutedphenyl or naphthyl, or phenyl or naphthyl substituted by one or more,e.g. 1 to 4, substituents selected from C₁-C₄-alkyl, hydroxy,C₁-C₄-alkoxy, halogen, or halo-C₁-C₄-alkyl. Preferably, aryl isunsubstituted phenyl or phenyl substituted by 1 or 2 substituentsselected from C₁-C₄-alkyl or halogen.

“Alkylene” denotes straight chain or branched alkylene which may be, forexample, C₁-C₁₀-alkylene such as methylene, ethylene, 1,2-propylene,1,3-propylene, butylene, pentylene, hexylene, heptylene, octylene,nonylene or decylene. Preferably alkylene is C₁-C₄-alkylene.

“Alkenylene” denotes straight chain or branched alkenylene which may be,for example, C₂-C₁₀-alkenylene such as vinylene, propenylene,butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenyleneor decenylene. Preferably alkenylene is C₂-C₄-alkenylene.

In formula I, n is 1 or 2, i.e. there are 2 or 4 CH₂ groups in the ringfused to the indicated benzene ring, so that ring is either a 5-memberedor 7-membered ring.

The group Ar in formula II in which R⁸ is —NHR¹⁸ and —NHR¹⁸ and R⁹together denote a 5- or 6-membered heterocycle may be, for example, agroup in which Y is carbon, R⁸ is —NHR¹⁸ and —NHR¹⁸ and R⁹ togetherdenote

-   a group of formula —NH—CO—R²³— where R²³ is an alkylene, alkenylene    or alkyleneoxy group,-   a group of formula —NH—SO₂—R²⁴ where R²⁴ is an alkyleneoxy group,-   a group of formula —NH—R²⁵(COOR²⁶)— where R²⁵ is an alkylene or    alkenylene group and R²⁶ is alkyl, or-   a group of formula —NH—CO—NH— or —NH—CO—S—,-   R¹⁰ is —OR¹⁹ where R¹⁹ is as hereinbefore defined,-   X is alkyl,-   p is 1, q is 1 and r is zero or 1.

The alkylene, alkenylene and alkyleneoxy groups preferably have 1 to 4carbon atoms.

Preferred groups Ar of formula II in which R⁸ is —NHR¹⁸, and —NHR¹⁸ andR⁹ together denote a 5- or 6-membered heterocycle, include groups inwhich

-   Y is carbon, R⁸ is —NHR¹⁸ and —NHR¹⁸ and R⁹ together denote a group    of formula —NH—CO—C(R²⁷)═C(R²⁸)— or —NH—CO—CH₂—O— or —NH—CO—CH₂— or    —NH—SO₂—CH₂—O— or —NH—C(COOR²⁶)═CH— or —NH—CO—NH— or —NH—CO—S— where    R²⁷ and R²⁸ are each independently hydrogen or C₁-C₄-alkyl and R²⁶    is C₁-C₄-alkyl, R¹⁰ is —OH, X is C₁-C₄-alkyl, p is 1, q is 1 and r    is zero or 1.

More preferred groups Ar of formula II where R⁸ is —NHR¹⁸, and —NHR¹⁸and R⁹ together denote a 5- or 6-membered heterocycle include those ofthe formulae

in which R²⁹, R³⁰ and R³¹ are each independently hydrogen orC₁-C₄-alkyl,

in which Z is —O—, —NH— or —S—.

The group Ar of formula II in which R⁸ is halogen and R⁹ is hydrogen maybe, for example, a group of formula II in which Y is carbon, R⁸ ishalogen, preferably chlorine, R⁹ is hydrogen, R¹⁰ is —NHR¹⁸ where R¹⁸ ishydrogen or C₁-C₄-alkyl, preferably hydrogen or methyl, X is halogen orhalomethyl, preferably chlorine or trifluoromethyl, and p, q and r areeach 1. Preferred groups Ar among such groups include those of formulae

The group Ar of formula II in which R⁸ is —OR¹³ and R⁹ is hydrogen maybe, for example, a group of formula II in which Y is carbon, R⁸ is —OR¹³where R¹³ is hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, —COR¹⁴where R¹⁴ is C₁-C₄-alkyl, C₆-C₁₀-aryl or —N(R¹⁵)R¹⁶ where R¹⁵ and R¹⁶are each independently hydrogen or C₁-C₄-alkyl, R¹⁰ is —OR¹⁹ or —NHR¹⁹where R¹⁹ is hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, or —COR²⁰where R²⁰ is —N(R²¹)R²², C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl orC₆-C₁₀-aryl and R²¹ and R²² are each independently hydrogen orC₁-C₄-alkyl, p and q are each 1 and r is zero. Preferred groups Ar amongsuch groups include those of formulae

The group Ar of formula II in which R⁸ is —CH₂OR¹³ may be, for example,a group of formula II in which Y is carbon, R⁸ is —CH₂OR¹³ where R¹³ ishydrogen, C₁-C₄-alkyl, or C₁-C₄-alkoxy-C₁-C₄-alkyl, R⁹ is hydrogen, R¹⁰is —OR¹⁹ where R¹⁹ is hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy-C₁-C₄-alkylor R¹⁰ is —NHR¹⁹ where R¹⁹ is hydrogen, C₁-C₄-alkyl or —COR²⁰ where R²⁰is C₁-C₄-alkyl, C₆-C₁₀-aryl or —N(R²¹)R²² where R²¹ and R²² are eachindependently hydrogen or C₁-C₄-alkyl, p and q are each 1 and r is zero;or a group of formula in which Y is nitrogen, R⁸ is —CH₂OR¹³ where R¹³is hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy-C₁-C₄-alkyl, R¹⁰ is —OR¹⁹ whereR¹⁹ is hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy-C₁-C₄-alkyl, p and r arezero and q is 1. Preferred groups Ar among such groups include those offormulae

The group Ar of formula II in which R⁸ is NHR¹³ may be, for example, agroup of formula II in which Y is carbon, R⁸ is NHR¹³ where R¹³ ishydrogen, C₁-C₁₀ alkyl, C₁-C₁₀ alkyl interrupted by 1 to 3 hetero atoms,—COR¹⁴ where R¹⁴ is hydrogen, C₁-C₁₀-alkyl or C₁-C₁₀-alkyl interruptedby 1 to 3 hetero atoms, or R¹³ is —C(═NH)R¹⁷, —SOR¹⁷ or —SO₂R¹⁷ whereR¹⁷ is C₁-C₁₀-alkyl or C₁-C₁₀-alkyl interrupted by 1 to 3 hetero atoms,R⁹ is hydrogen, R¹⁰ is —OR¹⁸ where R¹⁸ is hydrogen, C₁-C₄-alkyl orC₁-C₄-alkoxy-C₁-C₄ alkyl, p and q are each 1 and r is zero. Preferredgroups Ar among such groups include those of formula

especially those where R¹³ is hydrogen, C₁-C₄-alkyl, —COR¹⁴ where R¹⁴ ishydrogen or C₁-C₄-alkyl, or R¹³ is —SO₂R¹⁷ where R¹⁷ is C₁-C₄-alkyl.

Especially preferred groups Ar are those of formulae III, IV, V, XII andXV as hereinbefore defined.

The group R¹ in formula I may be, for example, hydrogen, hydroxy orC₁-C₄-alkoxy such as methoxy, ethoxy, isopropoxy, n-butoxy ortert-butoxy. Preferably, R¹ is hydroxy.

When R¹ is hydroxy or alkoxy, the carbon atom in formula I marked withan asterisk * preferably has the R configuration.

The groups R² and R³ in formula I may be, for example, eachindependently hydrogen or C₁-C₄-alkyl, e.g. methyl or ethyl. In most ofthe preferred embodiments of the invention, R² is hydrogen and R³ ishydrogen or methyl.

The groups R⁴, R⁵, R⁶ and R⁷ in formula I may be, for example, eachindependently hydrogen, chlorine, fluorine, chloromethyl,trifluoromethyl, hydroxy, C₁-C₁₀-alkoxy, C₁-C₁₀-alkyl, C₁-C₁₀-alkylinterrupted by one or more oxygen or sulfur atoms or one or more NH, SOor SO₂ groups, C₂-C₄-alkenyl, trimethylsilyl, triethylsilyl, phenyl,carboxy, C₁-C₄-alkoxycarbonyl, —CONR¹¹R¹² (where R¹¹ and R¹² are eachindependently hydrogen or C₁-C₄-alkyl), or R⁴ and R⁵, R⁵ and R⁶ or R⁶and R⁷, together with the carbon atoms to which they are attached, maydenote a 5- or 6-membered carbocyclic ring, which is preferably acycloaliphatic ring which is preferably saturated, or a 5- or 6-memberedO-heterocyclic ring containing one or two oxygen atoms. Preferably, R⁴,R⁵, R⁶ and R⁷ are each hydrogen or are such that the benzene ring towhich they are attached is symmetrically substituted, i.e. either (a) R⁴and R⁷ are identical and R⁵ and R⁶ are identical or together denote asymmetrical ring, or (b) R⁴ and R⁵ together and R⁶ and R⁷ togetherdenote identical rings. More preferably, R⁴ and R⁷ are identical and areeach hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, and either R⁵ and R⁶ areidentical and are each hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy orC₁-C₄-alkoxy-C₁-C₄-alkyl, or R⁵ and R⁶ together denote —(CH₂)_(s)— or—O(CH₂)_(t)O— where s is 3 or 4 and t is 1 or 2.

Especially preferred compounds of the invention include compounds offormula I in which Ar is a group of formula III, IV, V, XII or XV, R¹ ishydroxy, R² and R³ are hydrogen, and R⁴ and R⁷ are identical and areeach hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, and either R⁵ and R⁶ areidentical and are each hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy orC₁-C₄-alkoxy-C₁-C₄-alkyl, or R⁵ and R⁶ together denote —(CH₂)₄— or—O(CH₂)₂O—, in free or salt or solvate form. In such compounds, thecarbon atom in formula I marked with an asterisk * preferably has the Rconfiguration. Specific especially preferred compounds are thosedescribed in the Examples hereinafter.

The compounds of formula (I) are capable of forming acid addition salts,particularly pharmaceutically acceptable acid addition salts.Pharmaceutically acceptable acid addition salts of the compound offormula I include those of inorganic acids, for example, hydrohalicacids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid orhydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; andorganic acids such as formic acid, acetic acid, propionic acid, butyricacid, benzoic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid,p-chlorobenzoic acid, diphenylacetic acid, triphenylacetic acid,1-hydroxynaphthalene-2-carboxylic acid,3-hydroxynaphthalene-2-carboxylic acid, aliphatic hydroxy acids such aslactic acid, citric acid, tartaric acid or malic acid, dicarboxylicacids such as fumaric acid, maleic acid or succinic acid; and sulfonicacids such as methanesulfonic acid or benzenesulfonic acid. These saltsmay be prepared from compounds of formula I by known salt-formingprocedures.

Suitable solvates are pharmaceutically acceptable solvates, preferablyhydrates.

The present invention also provides a process for the preparation ofcompounds of formula I in free or salt or solvate form. They can beprepared by a process comprising:

-   (a) for the preparation of a compound where R¹ is hydroxy, either-   (i) reacting a compound of formula

with a compound of formula

where Ar¹ is Ar as hereinbefore defined or a protected form thereof, R²,R³, R⁴, R⁵, R⁶, R⁷ and n are as hereinbefore defined and R³² ishydrogen, or an amine-protective group, or

-   (ii) reducing a compound of formula

where Ar¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as hereinbefore defined, toconvert the indicated keto group into —CH(OH)—; or

-   (b) for the preparation of a compound where R¹ is hydrogen, reducing    a corresponding compound of formula I where R¹ is hydroxy; or-   (c) for the preparation of a compound of formula I where R¹ is    alkoxy, either (i) O-alkylating a corresponding compound of formula    I where R¹ is hydroxy or (ii) reacting a corresponding compound    having a leaving moiety instead of R¹ with an alcohol of formula R¹H    where R¹ is alkoxy;-   and, optionally, converting a resultant compound of formula I in    protected form into a corresponding compound in unprotected form;-   and recovering the resultant compound of formula I in free or salt    or solvate form.

Process variant (a)(i) may be carried out using known procedures forepoxide-amine reactions. It is conveniently carried out without asolvent or in an inert solvent, for example a hydrocarbon such astoluene or an alcohol such as n-butanol. The reaction temperature isconveniently from 25° C. to: 200° C., preferably from 80° C. to 150° C.The temperature may be achieved by conventional heating or by microwaveirradiation.

Process variant (a)(ii) may be carried out using conventional methods,for example by reaction with sodium borohydride under conventionalconditions.

Process variant (b) may be carried out using known procedures forreduction of secondary alcohols to hydrocarbons. Process variant (c)(i)may be carried out using known procedures for O-alkylation, for exampleby reaction with an alkylating agent such as an alkyl halide under knownconditions. Process variant (c)(ii) may be effected using knownprocedures for benzylic displacement reactions, the leaving moiety beinge.g. tosylate, mesylate, halogen or hydroxy.

Compounds of formula I in free form may be converted into salt orsolvate forms, and vice versa, in a conventional manner.

Compounds of the invention can be recovered from the reaction mixtureand purified in a conventional manner. Isomers, such as enantiomers, maybe obtained in a conventional manner, e.g. by fractional crystallizationor asymmetric synthesis from corresponding asymmetrically substituted,e.g. optically active, starting materials.

Compounds of formula XVI are known compounds or can be prepared byprocesses analogous to those used for the preparation of the knowncompounds, for example the procedures described in Journal of MedicinalChemistry 1987, 30, 1563-1566. Compounds of formula XVI in which thecarbon atom indicated by the asterisk * is chiral may be prepared from acompound of formula

where Ar¹ and R² are as hereinbefore defined and L is a leaving atom orgroup, as described in WO95/25104.

Compounds of formula XVI may alternatively be prepared by epoxidation ofa compound of formulaAr¹—CH═CH—R²  XXwhere Ar¹ and R² are as hereinbefore defined, using conventionalprocedures, such as those used in the Examples hereinafter.

Compounds of formula XX are known or may be prepared by methodsanalogous to those used for the preparation of known compounds, forexample those used in the Examples hereinafter.

Compounds of formula XVII are known or may be prepared by methodsanalogous to those used for the preparation of the known compounds. R³²as an amine-protective group in formula XVII may be a known such group,for example as described in Protective Groups in Organic Synthesis, T.W. Greene, P. G. M. Wuts, John Wiley & Sons Inc, Second Edition, 1991,preferably benzyl or trifluoroacetyl.

For example, compounds of formula XVII, where R³ is hydrogen, may beprepared by reducing an oxime of formula

where R⁴, R⁵, R⁶, R⁷ and n are as hereinbefore defined. The reductionmay be carried out by conventional methods for reducing oximes toamines. For example, the reduction may be carried out by catalytichydrogenation, preferably using palladium on charcoal as the catalyst.The hydrogenation may be effected using known procedures, for example asdescribed by RD. Sindelar et al, J. Med. Chem. (1982), 25(7), 858-864.Oximes of formula XXI may be prepared as described by Sindelar et al,op. cit., or by analogous procedures.

Compounds of formula XVII where R⁴ and R⁷ are hydrogen can be preparedby reacting a compound of formula

with a compound of formulaR⁵—C≡C—R⁶  XXIIIwhere R³, R⁵, R⁶, R³² and n are as hereinbefore defined. The reactionmay be carried out in the presence of a catalyst such astris(triphenylphosphine)rhodium chloride. The reaction temperature maybe, for example, from 60 to 120° C. The reaction is conveniently carriedout in an inert solvent, for example ethanol, when the reactiontemperature is conveniently about the reflux temperature of the solvent.The reaction may be carried out using known procedures, for example asdescribed in WO96/23760. Where R⁵ and R⁶ are trialkylsilyl, the reactionbetween the compounds of formulae XXII and XXIII may be carried out inthe presence of a metal carbonyl complex catalyst, for example using theprocedure described by K. P. C. Vollhardt and R. Hillard, J. Am. Chem.Soc. 1977, 99(12), 4058, or an analogous procedure. Compounds of formulaXXII may be prepared as described in WO96/23760 or by analogousprocedures. Compounds of formula XXIII are known or may be prepared byknown procedures.

Compounds of formula XVII where R³ is alkyl, particularly methyl, and nis 1 may be prepared by amination of the corresponding2-alkyl-indan-1-one using ammonia and K₃FeCN₆, e.g. by the procedure ofFornum and Carlson, Synthesis 1972, 191.

Compounds of formula XVII as hereinbefore defined where R⁴, R⁵, R⁶ andR⁷ are such that the benzene ring to which they are attached issymmetrically substituted are novel, other than the compounds where R⁴,R⁵, R⁶, R⁷ and R³⁰ are each hydrogen, where R⁴ and R⁷ are methyl ormethoxy when R⁵, R⁶ and R³⁰ are each hydrogen, and where R⁴, R⁷ and R³⁰are hydrogen when R⁵ and R⁶ are each hydroxy, fluorine or chlorine. Inparticular, preferred intermediates of formula XVII are novel where (i)R⁴ and R⁷ are each hydrogen and R⁵ and R⁶ are either each C₂-C₄-alkyl,C₂-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl or R⁵ and R⁶ together denote—(CH₂)_(s)— or —O(CH₂)_(t)O— where s is 1 to 4 and t is 1 or 2; or (ii)R⁴ and R⁷ are each C₂-C₄-alkyl or C₂-C₄-alkoxy and R⁵ and R⁶ are eithereach hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy and R⁵ and R⁶ are either eachhydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy, or C₁-C₄-alkoxy-C₁-C₄-alkyl or R⁵and R⁶ together denote —(CH₂)_(s)— or —O(CH₂)_(t)O— where s is 1 to 4and t is 1 or 2.

Compounds of formula XVII are novel compounds which may be prepared byreaction of a compound of formulaAr¹—CO—Hal  XXIVwhere Ar¹ is as hereinbefore defined and Hal is a halogen atom,preferably chlorine or bromine, with a compound of formula XVII ashereinbefore defined. The reaction may be carried out using conventionalprocedures, for example those described by Yoshizaki et al, J. Med. Chem(1976), 19(9), 1138-42.

Where desired, the protection of any reactive group may be carried outat any appropriate stage in the above processes. The protecting group issuitably one used conventionally in the art and may be introduced andremoved using conventional procedure. For example, when a hydroxy groupin Ar¹ is protected by a benzyl group, the latter may be removed bycatalytic hydrogenation in the presence of palladium on charcoal usingconventional procedures, such as those used hereinafter in the Examples.

Compounds of formula I in free, salt or solvate form are useful aspharmaceuticals. Accordingly the invention also provides a compound offormula I in free, salt or solvate form for use as a pharmaceutical. Thecompounds of formula I in free, salt or solvate form, hereinafterreferred to alternatively as “agents of the invention”, have goodβ2-adrenoreceptor agonist activity. The β2 agonist activity, onset ofaction and duration of action of the agents of the invention may betested using the guinea pig tracheal stip in vitro assay according tothe procedure of R. A. Coleman and A. T. Nials, J. Pharmacol. Methods(1989), 21(1), 71-86. The binding potency and selectivity for theβ2-adrenoreceptor relative to the β1-adrenoreceptor can be measured by aclassical filtration binding assay according to the procedure of CurrentProtocols in Pharmacology (S. J. Enna (editor-in-chief) et al, JohnWiley & Son, Inc, 1998), or by cAMP determination in cells expressingβ2- or β1-adrenoceptor, according to the procedure of B. January et al,British J. Pharmacol. 123: 701-711 (1998).

The agents of the invention commonly have a rapid onset of action andhave a prolonged stimulating action on the β2-adrenoreceptor, compoundsof the Examples hereinbelow having Ki (β2) values of the order of 0.1 to1000 nM, having durations of action of the order of 1 to greater than 12hours, and having binding selectivites for the β2-adrenoreceptorrelative to the β1-adrenoreceptor from 1.5 to 500. For example, thecompounds of Examples 1, 2, 4, 5, 6, 8, and 27 have β2 and β1 bindingpotencies, measured by cAMP determination in cells expressing β2- andβ1-adrenoreceptors, represented by EC₅₀ values (β2/β1) (in nM) of0.92/9.52, 0.23/1.25, 6.07/14.5, 0.79/6.10, 0.3/3.60, 0.57/8.46 and0.012/0.5 respectively. The compounds of Examples 2, 4, 5, 27 and 29have T(50%) times (in minutes) of >400 at 71 nM concentration, 82 at 100nM, 444 at 100 nM, 222 at 1.0 nM and 279 at 10 nM respectively in theguinea pig tracheal strip assay, where T(50%) is the time for inhibitionof contraction to decay to 50% of its maximum value.

Having regard to their β2 agonist activity, the agents of the inventionare suitable for use in the treatment of any condition which isprevented or alleviated by activation of the β2-adrenoreceptor. In viewof their long acting selective β2 agonist activity, the agents of theinvention are useful in the relaxation of bronchial smooth muscle andthe relief of bronchoconstriction. Relief of bronchoconstriction can bemeasured in models such as the in vivo plethysmography models of Chonget al, J. Pharmacol. Toxicol. Methods 1998, 39, 163-168, Hammelmann etal, Am. J. Respir. Crit. Care Med., 1997, 156,766-775 and analogousmodels. The agents of the invention are therefore useful in thetreatment of obstructive or inflammatory airways diseases. In view oftheir long duration of action, it is possible to administer the agentsof the invention once-a-day in the treatment of such diseases. Inanother aspect, agents of the invention commonly exhibit characteristicsindicating a low incidence of side effects commonly encountered with β2agonists such as tachycardia, tremor and restlessness, such agentsaccordingly being suitable for use in on demand (rescue) treatment aswell as prophylactic treatment of obstructive or inflammatory airwaysdiseases.

Treatment of a disease in accordance with the invention may besymptomatic or prophylactic treatment. Inflammatory or obstructiveairways diseases to which the present invention is applicable includeasthma of whatever type or genesis including both intrinsic(non-allergic) asthma and extrinsic (allergic) asthma. Treatment ofasthma is also to be understood as embracing treatment of subjects, e.g.of less than 4 or 5 years of age, exhibiting wheezing symptoms anddiagnosed or diagnosable as “wheezy infants”, an established patientcategory of major medical concern and now often identified as incipientor early-phase asthmatics. (For convenience this particular asthmaticcondition is referred to as “wheezy-infant syndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include adult respiratorydistress syndrome (ARDS), chronic obstructive pulmonary or airwaysdisease (COPD or COAD), including chronic bronchitis, or dyspneaassociated therewith, emphysema, as well as exacerbation of airwayshyperreactivity consequent to other drug therapy, in particular otherinhaled drug therapy. The invention is also applicable to the treatmentof bronchitis of whatever type or genesis including, e.g., acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Furtherinflammatory or obstructive airways diseases to which the presentinvention is applicable include pneumoconiosis (an inflammatory,commonly occupational, disease of the lungs, frequently accompanied byairways obstruction, whether chronic or acute, and occasioned byrepeated inhalation of dusts) of whatever type or genesis, including,for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,siderosis, silicosis, tabacosis and byssinosis.

Having regard to their β2 agonist activity, the agents of the inventionare also useful in the treatment of a condition requiring relaxation ofsmooth muscle of the uterus or vascular system. They are thus useful forthe prevention or alleviation of premature labour pains in pregnancy.They are also useful in the treatment of chronic and acute urticaria,psoriasis, allergic conjunctivitis, actinitis, hay fever, andmastocytosis.

The agents of the invention are also useful as co-therapeutic agents foruse in conjunction with anti-inflammatory or bronchodilatory drugsubstances, particularly in the treatment of obstructive or inflammatoryairways diseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Anagent of the invention may be mixed with the anti-inflammatory orbronchodilatory drug in a fixed pharmaceutical composition or it may beadministered separately, before, simultaneously with or after theanti-inflammatory or bronchodilatory drug. Such anti-inflammatory drugsinclude steroids, in particular glucocorticosteroids such as budesonide,beclamethasone, fluticasone or mometasone, and dopamine receptoragonists such as cabergoline, bromocriptine or ropinirole. Suchbronchodilatory drugs include anticholinergic or antimuscarinic agents,in particular ipratropium bromide, oxitropium bromide and tiotropiumbromide. Combinations of agents of the invention and steroids may beused, for example, in the treatment of COPD or, particularly, asthma.Combinations of agents of the invention and anticholinergic orantimuscarinic agents or dopamine receptor agonists may be used, forexample, in the treatment of asthma or, particularly, COPD.

In accordance with the foregoing, the present invention also provides amethod for the treatment of an obstructive or inflammatory airwaysdisease which comprises administering to a subject, particularly a humansubject, in need thereof a compound of formula I, or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore described. Inanother aspect, the invention provides a compound of formula I, or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedescribed for use in the preparation of a medicament for the treatmentof an obstructive or inflammatory airways disease.

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; topically to the skin, forexample in the treatment of psoriasis; intranasally, for example in thetreatment of hay fever; or, preferably, by inhalation, particularly inthe treatment of obstructive or inflammatory airways diseases.

In a further aspect, the invention also provides a pharmaceuticalcomposition comprising a compound of formula I in free form or in theform of a pharmaceutically acceptable salt or solvate thereof,optionally together with a pharmaceutically acceptable diluent orcarrier therefor. Such compositions may be prepared using conventionaldiluents or excipients and techniques known in the galenic art. Thusoral dosage forms may include tablets and capsules. Formulations fortopical administration may take the form of creams, ointments, gels ortransdermal delivery systems, e.g. patches. Compositions for inhalationmay comprise aerosol or other atomizable formulations or dry powderformulations.

The invention also includes (A) a compound of formula I as hereinbeforedescribed in free form, or a pharmaceutically acceptable salt or solvatethereof, in inhalable form; (B) an inhalable medicament comprising sucha compound in inhalable form together with a pharmaceutically acceptablecarrier in inhalable form; (C) a pharmaceutical product comprising sucha compound in inhalable form in association with an inhalation device;and (D) an inhalation device containing such a compound in inhalableform.

Dosages employed in practising the invention will of course varydepending, for example, on the particular condition to be treated, theeffect desired and the mode of administration. In general, suitabledaily dosages for administration by inhalation are of the order of from1 to 5000 μg.

The invention is illustrated by the following Examples. Compounds usedin the Examples are prepared as follows:

Intermediate 1-5,6-Diethyl-indan-2-ylamine hydrochloride Preparation1-3-chloro-1-(3,4-diethylphenyl)-1-propanone

1,2-Diethylbenzene (10.9 g, 74.6 mmol) and propionyl chloride. (9.7 g,74.6 mmol) are added dropwise to AlCl₃ (22.3 g, 167.8 mmol) innitromethane (75 mL) over 30 min. The reaction mixture is stirred atroom temperature for 2 hours, after which 70 g of ice and 14 mLconcentrated sulphuric acid are added. The aqueous phase is extractedwith ether, and the combined organic phases extracted with 2N HCl andsaturated aqueous NaCl. The organic phase is further treated withactivated charcoal, magnesium sulphate, and filtered, and the solventremoved in vacuo.

1H-NMR (CDCl₃) ppm: 7.8 (1H, s, Ar); 7.7 (1H, d, Ar); 7.2 (1H, d, Ar);3.9 (2H, t, CH₂); 3.4 (2H, t, CH₂); 2.8 (4H, q, CH₂CH₃); 1.2 (6H, m,CH₃).

Preparation 2-2,3-dihydro-5,6-diethyl-1H-inden-1-one

3-chloro-1-(3,4-diethylphenyl)-1-propanone (15.5 g) is dissolved in 66mL concentrated sulphuric acid and heated to 90° C. for 4 hours. Thereaction mixture is cooled, ice (70 g) is added, and the aqueoussolution extracted twice with toluene. The organic layer is washed withsodium bicarbonate, saturated aqueous NaCl, and treated with activatedcharcoal and magnesium suphate. After filtration, the solvent is removedin vacuo. The product is purified by flash column chromatography(silica, hexane/ethylacetate 10:1), and further crystallised in hexane.

1H-NMR (CDCl3) ppm: 7.6 (1H, s, Ar); 7.3 (1H, d, Ar); 3.1 (2H, m, CH₂);2.7 (6H, m, CH₂+CH₂CH₃); 1.2 (6H, m, CH₃).

Preparation 3-5,6-Diethyl-3-oxime-1H-indene-1,2(3H)-dione

2,3-Dihydro-5,6-diethyl-1H-inden-1-one (5 g, 26 mmol) in methanol (75mL) is brought to 40° C., n-butyl nitrite (3.0 g, 28.6 mmol) is addeddropwise, followed by the addition of concentrated HCl (1.25 mL). After1 hour, the reaction is brought to room temperature and the precipitatedproduct filtered off, washed with ice-cold methanol and dried.

1H-NMR (d6-DMSO) ppm: 12.6 (1H, s, OH); 7.4 (1H, s, Ar); 7.3 (1H, d,Ar); 3.6 (2H, s, CH₂); 2.6 (4H, m, CH₂CH₃); 1.1 (6H, m, CH₃).

Preparation 4-5,6-Diethyl-indan-2-ylamine Hydrochloride

5,6-Diethyl-3-oxime-1H-indene-1,2(3H)-dione (4.5 g) is added to amixture of acetic acid (150 mL), and concentrated sulphuric acid (4.5mL). Pd/C₅% (1.5 g) is added, the reaction mixture degassed withnitrogen, and hydrogenated for 5 hours. The catalyst is then removed byfiltration, the pH brought to pH 10 with 4M NaOH, and the solutionextracted with chloroform. The organic phase is dried with magnesiumsulphate, and the solvent removed in vacuo. The residue is redisolved ina minimum amount of ether, and HCl saturated ether added. The whiteprecipitate is filtered and dried to yield the HCl salt of5,6-diethyl-indan-2-ylamine, a compound of formula XVII where R³, R⁴ andR⁷ are H, R⁵ and R⁶ are each CH₃CH₂—, R³⁰ is hydrogen and n is 1.

1H-NMR (d6-DMSO) ppm: 8.7 (3H, bd s, NH₃); 7.3 (2H, s, Ar); 4.2 (1H, bds, CH); 3.5 (2H, dd, CH₂); 3.3 (2H, dd, CH₂); 2.8 (4H, q, CH₂CH₃); 1.4(6H, t, CH₃).

Other compounds of formula XVII are prepared by procedures analogous tothose used for Intermediate 1 or starting from available compounds andusing procedures analogous to Preparations 3 and 4. These compounds offormula XVII are shown in the following table, R³ being hydrogen and nbeing 1 for all compounds.

Intermediate R⁴ R⁵ R⁶ R⁷ 2 CH₃CH₂ H H CH₃CH₂ 3 H —(CH₂)₄— H 4 H—O(CH₂)₂O— H 5 H CH₃(CH₂)₃ CH₃(CH₂)₃ H 6 H CH₃(CH₂)₂ CH₃(CH₂)₂ H 7 HCH₃O CH₃O H

Intermediate 2: ES+MS m/e (MH+): 204

Intermediate 3: 1H-NMR (d6-DMSO) ppm: 8.1 (3H, bd s, NH₃); 6.9 (2H, s,Ar); 3.9 (1H, bd s, CH); 3.2 (2H, dd, CH₂); 2.8 (2H, dd, CH₂); 2.7 (4H,m, CH₂Ar); 1.7 (6H, t, CH₂).

Intermediate 4: 1H-NMR (d6-DMSO) ppm: 8.3 (3H,bds, NH₃); 6.85 (2H, s,Ar); 4.2 (4H, s,2CH₂); 3.1 (2H, dd, CH₂); 2.85 (2H, dd, CH₂).

Intermediate 5: 1H-NMR (d6-DMSO) ppm: 6.9 (2H, s, Ar); 3.8 (1H, m, CH);3.1 (2H, dd, CH₂); 2.6 (2H, dd, CH₂); 2.5 (4H, t, 2CH₂); 1.65 (2H, bds,NH₂); 1.55 (4H, m, 2CH₂); 1.4 (4H, m, 2CH₂); 0.95 (6H, t, 2CH₃).

Intermediate 6: 1H-NMR (d6-DMSO) ppm: 8.1 (3H, bd s, NH₃); 7.0 (2H, s,Ar); 3.9 (1H, bd s, CH); 3.2 (2H, dd, CH₂); 2.8 (2H, dd, CH₂); 2.5 (4H,q, EtCH₂Ar); 1.6 (4H, q, CH₂), 0.9 (6H, t, CH₃).

Intermediate 7: 1H-NMR (d6-DMSO) ppm: 8.3 (3H, bd s, NH₃), 6.9 (2H, s,H—Ar), 3.9 (1H, bd m, CHN), 3.7 (6H, s, CH₃O), 3.2 (2H, dd, CH₂), 2.9(2H, dd, CH₂).

Intermediate 8-2-(Trifluoroacetylamino)-5,6-bis(methoxymethyl)indane

According to the procedure of Magnus et. al (Tetrabed. Lett., 34, 23-26(1993)) a solution of commercially available 1,4-dimethoxy-2-butyne(1.32 g, 11.5 mmol) in nitrogen-degassed ethanol is heated to 80° C.with stirring under a nitrogen atmosphere.Tris(triphenylphosphine)rhodium chloride (64 mg, 0.07 mmol) and asolution of 2,2,2-trifluoro-N-[1-(2-propynyl)-3-butynyl]-acetamide (470mg, 2.32 mmol; prepared from literature procedure: Romero, Arthur G.;Leiby, Jeffrey A PCT Int. Appl. WO 9623760) in nitrogen-degassed ethanol(2 ml) are added in portions over 2 hours. The mixture is stirred undernitrogen at 80° C. for a further 3 hours. The solvent is removed undervacuo and the residue is purified by flash chromatography on silica gel,eluting with hexanelethyl acetate (2:1).

¹H-NMR (CDCl₃) ppm: 2.9 (2H, dd), 3.35 (2H, dd), 3.45 (6H, s), 4.57 (4H,s), 4.85 (1H, m), 6.4 (1H, br s), 7.30 (2H, s).

Intermediate 9-2-Amino-5,6-bis(methoxymethyl)indane

A solution of potassium hydroxide (150 mg, 2.60 mmol) in water (0.5 ml)is added to a solution of2-(trifluoroacetylamino)-5,6-bis(methoxymethyl)indane (240 mg, 0.75mmol) in methanol (3 mL) and the mixture is heated at reflux for 2.5hours. The solvent was removed in vacuo and the residue is partitionedbetween aqueous sodium hydroxide (10 mL) and ethyl acetate (20 mL). Theorganic extract is dried. (MgSO₄) and the solvent is removed in vacuo toleave the product as a dark oil.

¹H-NMR (CDCl₃) ppm: 2.60 (2H, dd), 3.10 (2H, dd), 3.33 (6H, s), 3.75(1H, m), 4.42 (4H, s), 7.17 (2H, s).

Intermediate 10-8-Hydroxy-5-[(indan-2-ylamino)-acetyl]-1H-quinolin-2-one

5-(Chloroacetyl)-8-hydroxy-2(1H)-quinolinone (25 mg, 0.105 mmol)prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru;Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki. J. Med. Chem.(1976), 19(9), 1138-42) is reacted neat with indan-2-ylamine (205 mg,1.21 mmol) at 25° C. for 2 hours. The reaction mixture is purified byflash chromatography (silica, CH₂Cl₂/methanol 9:1). ES+ MS m/e 335(MH+).

Intermediate 11

This compound of formula XVIII where Ar is a group of formula III, R²⁷,R²⁸ and R²⁹ are hydrogen, R², R³, R⁴ and R⁷ are hydrogen, and R⁵ and R⁶are each methoxy, is prepared by a procedure analogous to that used forpreparation of Intermediate 10. ES+MS m/e (MH⁺): 395.

Intermediate 12-8-Benzyloxy-3-methyl-5-oxiranyl-1H-quinolin-2-one

8-Hydroxy-3-methyl-1H-quinolin-2-one is prepared according to theprocedure of Wang et al (T.-C. Wang, Y.-L. Chen, K.-H. Lee, C.-C. IzengSynthesis 1997, 87-90.).

¹H-NMR (d4-CH₃OH) ppm: 2.14 (s, 3H), 6.84-6.89 (m, 1H), 6.95-7.03 (m,2H), 6.90 (s, 1H), 7.71 (s, 1H).

8-Benzyloxy-3-methyl-1H-quinolin-2-one

Benzyl bromide (1.28 mL) is added to a suspension of potassium carbonate(2.98 g) in a solution of 8-hydroxy-3-methyl-1H-quinolin-2-one (1.26 g)in acetone (36 mL) at room temperature. The reaction mixture is refluxedfor 18 hours, filtered, evaporated and purified by flash columnchromatography on silica gel, eluting with 2% methanol indichloromethane.

¹H-NMR (CDCl₃) ppm: 2.11 (s, 3H), 5.13 (s, 2H), 6.92-6.98 (m, 1H),7.02-7.08 (m, 2H), 7.29-7.40 (m, 5H), 7.57 (s, 1H), 9.23 (s, 1H).

8-Benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one

A solution of bromine (0.57 g) in acetic acid (2 mL) is added dropwiseto a solution of 8-benzyloxy-3-methyl-1H-quinolin-2-one (0.94 g) andsodium acetate (0.96 g) in acetic acid (12 mL) at room temperature. Thereaction mixture is stirred at room temperature for 3 hours, evaporated,the residue partitioned between water (5 mL) and ethyl acetate (5 mL),extracting a further 2× with ethyl acetate (5 mL). Combined organicextracts are dried over magnesium sulphate and purified by flash columnchromatography on silica gel, eluting with 2% methanol indichloromethane.

¹H-NMR (CDCl₃) ppm: 2.27 (s, 3H), 5.18 (s, 2H), 6.83 (d, 1H), 7.39 (d,1H), 7.37-7.41 (m, 5H), 7.91 (s, 1H), 9.08 (s, 1H).

8-Benzyloxy-3-methyl-5-vinyl-1H-quinolin-2-one

Palladium terakis(triphenylphosphine) (30 mg) is added to a solution of8-benzyloxy-5-bromo-3-methyl-1H-quinolin-2-one (239 mg) andtributylvinyltin (203 μL) in toluene (7 mL) at room temperature. Thereaction mixture is heated for 2 hours at 100° C., cooled to roomtemperature, evaporated and the product purified by flash columnchromatography on silica gel, eluting with 2% ethyl acetate indichloromethane.

¹H-NMR (CDCl₃) ppm: 2.24 (s, 3H), 5.18 (s, 2H), 5.32-5.39 (m, 1H),5.61-5.68 (m, 1H), 6.95 (d, 1H), 7.09-7.20 (m, 1H), 7.21-7.26 (m, 2H),7.31-7.43 (m, 4H), 7.89 (s, 1H), 9.20 (s, 1H).

8-Benzyloxy-3-methyl-5-oxiranyl-1H-quinolin-2-one

To 8-benzyloxy-3-methyl-5-vinyl-1H-quinolin-2-one (300 mg) is added to a0.1M solution of dimethyldioxirane in acetone (12.4 mL). After stirringat room temperature for 2 hours, the solvent is removed in vacuo toyield the product.

¹H-NMR (CDCl₃) ppm: 2.23 (s, 3H), 2.77-2.81 (m, 1H), 3.18-3.23 (m, 1H),4.17-4.21 (m, 1H), 5.18 (s, 2H), 6.91 (d, 1H), 7.01 (d, 1H), 7.93 (s,1H), 9.10 (s, 1H).

Intermediate13-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3-methyl-1H-quinolin-2-one

A solution of Intermediate 12 (65 mg) and 5,6-diethyl-indan-2-ylamine(120 mg) in DMSO (1.5 mL) is heated for 18 hours at 90° C. The solventis removed in vacuo, and the product purified by flash chromatography onsilica gel, eluting with 10% methanol in dichloromethane.

¹³C-NMR (d4-CH₃OH) ppm: 15.96, 17.14, 26.33, 36.77, 53.34, 59.82, 67.33,71.73, 112.09, 118.98, 121.73, 125.42, 128.74, 129.24, 129.47, 129.61,131.84, 134.56, 137.52, 137.64, 142.29, 145.94, 164.02.

Intermediate 14-8-Methoxymethoxy-6-methyl-5-oxiranyl-1H-quinolin-2-one

8-Hydroxy-6-methyl-1H-quinolin-2-one is prepared according to theprocedure of Wang et al (T.-C. Wang, Y.-L. Chen, K.-H. Lee, C.-C. IzengSynthesis 1997, 87-90.).

¹H-NMR (d6-DMSO) ppm: 2.26 (s, 3H), 6.45 (d, 1H), 6.79 (s, 1H), 6.90 (s,1H), 7.78 (d, 1H).

5-Bromo-8-hydroxy-6-methyl-1H-quinolin-2-one

A 45% solution of hydrobromic acid in acetic acid (324 μL) is addeddropwise to a solution of 8-hydroxy-6-methyl-1H-quinolin-2-one (316 mg)in dimethylsulphoxide (9 mL) at room temperature. The reaction mixtureis allowed to stand for 18 hours at room temperature and the solventremoved in vacuo.

¹H-NMR (d6-DMSO) ppm: 2.33 (s, 3H), 6.58 (d, 1H), 6.92 (s, 1H), 8.03 (d,1H), 10.44 (s, 1H), 10.67 (s, br, 1H).

5-Bromo-8-methoxymethoxy-6-methyl-1H-quinolin-2-one

Methoxymethyl chloride (410 μL) was added to a suspension of potassiumcarbonate (1.24 g) in a solution of5-bromo-8-hydroxy-6-methyl-1H-quinolin-2-one (480 mg) indimethylformamide (9 mL) at 0° C. The reaction mixture is stirred for 18hours at room temperature, filtered, the solvent removed in vacuo, andthe product purified by flash column chromatography on silica gel,eluting with 2% methanol in dichloromethane.

¹³C-NMR (CDCl₃) ppm: 23.42, 56.52, 95.07, 115.78, 116.19, 119.32,123.30, 128.13, 132.14, 139.78, 141.78, 161.32.

8-Methoxymethoxy-6-methyl-5-vinyl-1H-quinolin-2-one

Bis-(triphenylphosphine)palladium (II) chloride (98 mg) is added to asolution of S-bromo-8-methoxymethoxy-6-methyl-1H-quinolin-2-one (410 mg)and tributylvinyltin (603 μL) in dimethylformamide (14 mL) at roomtemperature. The reaction mixture is heated for 24 hours at 90° C.,evaporated and purified by flash column chromatography on silica gel,eluting with 2% methanol in dichloromethane.

¹H-NMR (CDCl₃) ppm: 2.19 (s, 3H), 3.41 (s, 3H), 5.18 (d, 1H), 5.20 (s,2H), 5.60 (d, 1H), 6.52 (d, 1H), 6.63-6.69 (m, 1H), 6.96 (s, 1H), 7.95(d, 1H), 9.78 (s, 1H).

8-Methoxymethoxy-6-methyl-5-oxiranyl-1H-quinolin-2-one is obtained from8-methoxymethoxy-6-methyl-5-vinyl-1H-quinolin-2-one

(186 mg) according to the last step of the procedure for Intermediate12.

¹H-NMR (CDCl₃) ppm: 2.38 (s, 3H), 2.68-2.72 (m, 1H), 3.19-3.23 (m, 1H),3.43 (s, 3H), 3.97-4.01 (m, 1H), 5.21 (s, 2H), 6.60 (d, 1H), 6.98 (s,1H), 8.22 (d, 1H), 9.09 (s, 1H).

Intermediate 15, (R)-2-(4-benzyloxy-3-nitrophenyl)-oxirane, is preparedaccording to the procedure of R. Hett et al, Tetrahedron Lett. (1997),38(7), 1125-1128.

Intermediate 16-(S)-8-Benzyloxy-5-oxiranyl-1H-quinolin-2-one8-Benzyloxy-5-((S)-2-chloro-1-hydroxy-ethyl)-1H-quinolin-2-one

(S)-2-methyl-CBS-oxazaborolidine, 1M in toluene (0.30 mL, 0.30 mmol) isadded to dry THF (tetrahydrofuran) (10 mL) in an oven dried flask.Borane-THF complex, 1M in THF (3.05 mL) is then added dropwise and thesolution is stirred at room temperature for 15 minutes and then cooledto 0° C. 8-Benzyloxy-5-chloroacetyl-1H-quinolin-2-one (1.00 g), preparedas described in WO95/25104, is then added in small portions over aperiod of 30 minutes. The reaction mixture is stirred at 0° C. Thereaction is shown to be complete by TLC (thin layer chromatography)after 15 minutes. The reaction mixture is quenched with methanol (1 mL),the solvent is removed in vacuo and the residue is partitioned between0.2M H₂SO₄ (100 mL) and CHCl₃ (100 mL). The organic layer is dried overMgSO₄, filtered and the solvent is removed in vacuo. Crystallised fromethyl acetate. TLC (silica, dichloromethane I methanol 25:1 R_(f)=0.30).

(S)-8-Benzyloxy-5-oxiranyl-1H-quinolin-2-one

8-Benzyloxy-5-((S)-2-chloro-1-hydroxy-ethyl)-1H-quinolin-2-one (0.55 g)is dissolved in acetone (20 mL). K₂CO₃ (0.58 g) is added and thereaction mixture is refluxed. The reaction is shown to be complete byTLC after 18 hours. The solvent is removed in vacuo and the residue ispartitioned between ethyl acetate (100 mL) and water (100 mL). Theorganic layer is dried over MgSO₄, filtered and the solvent is removedin vacuo. The product is triturated with diethyl ether, filtered anddried. TLC (silica, dichloromethane/methanol 25:1 R_(f)=0.45).

Intermediate 17-6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-ylamineBenzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine

5,6,8,9-Tetrahydro-benzocyclohepten-7-one (3.00 g) and benzylamine (2.00g) are dissolved in ethanol (50 mL). A catalytic amount of 10% palladiumon charcoal is added and the reaction mixture is placed under anatmosphere of hydrogen. The reaction mixture is stirred at r.t. Thereaction is shown to be complete by TLC after 24 hours. The catalyst isfiltered off and the solvent is removed in vacuo. The product is notpurified further. TLC (silica, n-hexane/ethyl acetate 1:2 R_(f)=0.50).

6,7,8,9-Tetrahydro-5H-benzocyclohepten-7-ylamine

Benzyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine (2.80 g) isdissolved in methanol (100 mL) and the compound is deprotected by addinga catalytic amount of 10% palladium on charcoal and placing the solutionunder an atmosphere of hydrogen. The reaction is shown to be complete byTLC after 24 hours. The catalyst is filtered off and the solvent isremoved in vacuo. The product is not purified further. TLC (silica,dichloromethane/methanol 25:1 R_(f)=0.15).

Intermediate 18-Benzyl-(5,6-diethyl-indan-2-yl)-amineN-(5,6-Diethyl-indan-2-yl)-benzamide

5,6-Diethyl-indan-2-ylamine (4.10 g) is dissolved in dichloromethane(DCM) (150 mL) and triethylamine (2.41 g) is added. Benzoyl chloride(3.20 g) is then added dropwise and the reaction mixture is stirred atroom temperature. The reaction is shown to be complete by TLC after 1hour. The solution is washed with 0.2M HCl (100 mL), water (100 mL) andbrine (100 mL). The organic layer is dried over MgSO₄, filtered and thesolvent is removed in vacuo. Crystallised from ethyl acetate. TLC(silica, dichloromethane/methanol 10:1 R_(f)=0.85).

Benzyl-(5,6-diethyl-indan-2-yl)-amine

N-(5,6-Diethyl-indan-2-yl)-benzamide (3.30 g) is dissolved in dry THF(100 mL). Lithium aluminium hydride, 1M in THF (22.52 ml) is then addeddropwise. The reaction mixture is stirred at 50° C. The reaction isshown to be complete by TLC after 6 hours. The reaction mixture isallowed to cool, poured slowly into ice-water (200 mL) and extractedwith diethyl ether (2×150 mL). The organic layer is dried over MgSO₄,filtered and the solvent is removed in vacuo. The product is notpurified further. TLC (silica, n-hexane/ethyl acetate 2:1 R_(f)=0.20).

Intermediate19-(R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol)

The title compound is prepared from Intermediate 15 (3.01 g) andIntermediate 18 (3.10 g) by an analogous procedure to that used toprepare(S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onein Example 19. The reaction is shown to be complete by TLC after 24hours. The product is purified by flash column chromatography (silica,n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane ethyl acetate 4:1R_(f)=0.25).

(R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanol

(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol(3.00 g) is dissolved in THF (50 mL) and toluene (50 mL). A catalyticamount of PtO₂ is added and the solution is stirred under an atmosphereof H₂. The reaction is shown to be complete by TLC after 6 hours. Thecatalyst is filtered off and the solvent is removed in vacuo. Theproduct is not purified further. TLC (silica, n-hexane/ethyl acetate 1:1R_(f)=0.75).

Intermediate20-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanone2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanone

1-(4-Benzyloxy-3-nitro-phenyl)-2-bromo-ethanone (2.00 g) (Preparedfollowing procedure; Hett, Robert; Fang, Qun Kevin; Gao, Yun; Hong,Yaping; Butler, Hal T.; Nie, Xiaoyi; Wald, Stephen A. Tetrahedron Lett.1997, 38, 1125-1128.) is dissolved in methymethylketone (100 mL).Triethylamine (0.64 g) is added followed bybenzyl-(5,6-diethyl-indan-2-yl)-amine (1.60 g). The reaction mixture isthen refluxed. The reaction is shown to be complete by TLC after 3hours. The solvent is removed in vacuo and the product is purified byflash column chromatography (silica, n-hexane ethyl acetate 4:1). TLC(silica, n-hexane/ethyl acetate 2:1 R_(f)=0.75).

1-(3-Amino-4-benzyloxy-phenyl)-2-[be1-(5,6-diethyl-indan-2-yl)amino]-ethanone is prepared from2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanone(1.50 g) by an analogous procedure to that used to prepare(R)-1-(3-Amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanolin Example 19. The reaction is shown to be complete by TLC after 48hours. The catalyst is filtered off and the solvent is removed in vacuo.The product is purified by flash column chromatography (silica,n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethyl acetate 2:1R_(f)=0.70).

¹H NMR [CDCl₃, 400 MHz] d 1.20 (6H, t), 1.60 (2H, broad), 2.60 (4H, q),3.00 (4H, m) 3.90 (6H, m), 5.15 (2H, s), 6.80 (1H, d), 6.95 (2H, s),7.30 (12H, m).

Intermediate 21-Benzyl-(4,5,6,7-tetramethyl-indan-2-yl)-amine

3-Chloro-1-(2,3,4,5-tetramethyl-phenyl)-propan-1-one is prepared from1,2,3,4-tetramethyl-benzene and 3-chloro propionyl chloride by aprocedure analogous to that of Preparation 1.

¹H NMR (CD₃OD) ppm: 7.5 (1H, s); 4.2. (2H, t); 3.6 (2H, t); 2.6 (3H, s);2.57 (3H, s); 2.52 (3H, s); 2.5 (3H, s).

4,5,6,7-Tetramethyl-indan-1-one is prepared from3-chloro-1-(2,3,4,5-tetramethyl-phenyl)-propan-1-one by a procedureanalogous to that of Preparation 2.

¹H NMR (CD₃OD) ppm: 3.2 (2H, t); 2.9 (2H, t); 2.85 (3H, s); 2.6 (3H, s);2.55 (3H, s); 2.5 (3H, s).

4,5,6,7-Tetramethyl-indan-1,2-dione 2-oxime is prepared from4,5,6,7-tetramethyl-indan-1-one by a procedure analogous to that ofPreparation 3.

¹H NMR (d6-DMSO) ppm: 12.4 (1H, s); 3.65 (2H, s); 2.7 (3H, s); 2.4 (3H,s); 2.3 (6H, s).

2-Amino-4,5,6,7-tetramethyl-indan-1-one hydrochloride is prepared from4,5,6,7-tetramethyl-indan-1,2-dione 2-oxime by a procedure analogous tothat of Preparation 4.

¹H NMR (d6-DMSO) ppm: 9.0 (3H, bd s); 4.5 (1H, bd t); 3.7 (1H, dd); 3.2(1H, dd); 2.8 (3H, s); 2.6 (3H, s); 2.5 (6H, 2 s).

N-(4,5,6,7-Tetramethyl-1-oxo-indan-2-yl)-benzamide

Benzoyl chloride (1.635 g) is added dropwise to4,5,6,7-tetramethyl-indan-1,2-dione 2-oxime (2.53 g) and triethylamine(2.25 g) in anhydrous dichloromethane (60 ml) at 0° C. The reactionmixture is stirred at room temperature for 1.5 hours after which thesolid product is filtered off and allowed to-stir with water (150 ml),refiltered and dried. The organic filtrate is washed with 1M HCl, 10%brine, saturated sodium bicarbonate solution, 10% brine and treated withmagnesium sulphate. After filtration, the solvent is removed in vacuoand the product triterated with diethyl ether, filtered and dried.

¹H NMR (CDCl₃) ppm: 7.8 (2H, d); 7.45 (1H, m), 7.4 (2H, m); 6.8 (1H, bdd); 4.6 (1H, m); 3.8 (1H, dd); 2.8 (1H, dd); 2.55 (3H, s); 2.25 (3H, s);2.15 (6H, 2 s).

N-(1-Hydroxy-4,5,6,7-tetramethyl-indan-2-yl)-benzamide

Sodium borohydride (213 mg) is added toN-(4,5,6,7-tetramethyl-1-oxo-indan-2-yl)-benzamide (495 mg) inchloroform (20 ml) and methanol (20 ml). The reaction mixture is stirredat room temperature for 2 hours, drowned with water (50 ml) andchloroform (20 ml) added. The aqueous phase is washed with chloroform(×2) and the organic layers combined, treated with magnesium sulphate,filtered and the solvent removed in vacuo.

¹H NMR (CDCl₃) ppm: 7.65 (2H, d); 7.4 (1H, m), 7.35 (2H, m); 6.3 (1H, bdd); 5.15 (1H, d); 4.5 (1H, m); 3.7 (1H, bd s); 3.5 (1H, dd); 2.65 (1H,dd); 2.25 (3H, s); 2.15 (9H, 3 s).

N-(4,5,6,7-Tetramethyl-indan-2-yl)-benzamide is prepared fromN-(1-Hydroxy-4,5,6,7-tetramethyl-indan-2-yl)-benzamide by a procedureanalogous to that of Preparation 4.

¹H NMR (CDCl₃) ppm: 7.65 (2H, d); 7.4 (1H, m), 7.3 (2H, m); 6.25 (1H, bdd); 4.85 (1H, m); 3.35 (1H, dd); 2.80 (1H, dd); 2.1 (12H, 2 s).

Benzyl-(4,5,6,7-tetramethyl-indan-2-yl)-anine

1M Lithium aluminium hydride (2.4 ml) in tetrahydrofuran is addeddropwise to a solution of N-(4,5,6,7-tetramethyl-indan-2-yl)-benzamide(352 mg) in anhydrous THF (10 ml) under nitrogen at room temperature.The reaction mixture is allowed to stir at 50° C. for 20 hours. After 4hours more 1M Lithium aluminium hydride (1.2 ml, 1.20 mmole) in THF isadded. On cooling the reaction mixture is quenched with ice water. Theaqueous phase is washed with diethyl ether (×3) and the organic layerscombined, treated with magnesium sulphate, filtered and the solventremoved in vacuo.

¹H NMR (CDCl₃) ppm: 7.25 (4H, m); 7.15 (1H, m); 3.8 (2H, s); 3.55 (1H,m); 3.1 (2H, dd); 2.7 (2H, dd); 2.1 (12H, 2 s).

Intermediate22-Benzyl-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-amine

According to the procedure of A. F. Abdel-Magid, et. al. J. Org. Chem.1996, 61, 3849-3862. triethylamine (0.87 mL, 6.17 mmol) is added to astirred suspension2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine in1,2-dichloroethane (30 mL) under nitrogen at room temperature.Benzaldehyde (0.52 mL, 5.14 mmol) is then added followed by sodiumtriacetoxyborohydride (1.64 g, 7.7 mmol) and acetic acid (0.44 mL, 7.7mmol). The reaction is stirred at room temperature for 18 hours. Afterdiluting with dichloromethane the mixture is washed with aqueous NaOH(50 mL, 1M) followed by brine. Removal of the solvent and chromatography(silica, ethyl acetate/hexane, 2:1) affords an oil.

¹H-NMR (CDCl₃) ppm: 1.70 (m, 4H), 2.65 (m, 4H), 2.68 (dd, 2H), 3.05 (dd,2H), 3.58 (m, 1H), 3.78 (s, 2H), 6.83 (s, 2H), 7.25 (m, 5H).

Intermediate 23-2-Methyl-indan-2-ylamine 2-Amino-2-methyl-indan-1-one

According to the procedure of Farnum et. al (Synthesis 1972, 191-192.),water (1.35 L) is stirred at 80° C. and de-gassed by periodic evacuatingand flushing with nitrogen (3×). K₃FeCN₆ (202 g, 615 mmol) and2-methyl-indan-1-one (20 g, 137 mmol) are added. The mixture is stirredrapidly under nitrogen at 80° C. while aqueous concentrated ammoniasolution (105 mL) is added over 30 minutes. Stirring is continued at 80°C. for 20 hours. When cool, the solution is made alkaline by addition ofsodium hydroxide (2 g) and extracted with ethyl acetate (2×200 mL). Theorganic extract is concentrated to a volume of 200 ml and the product isextracted into aqueous HCl (200 mL, 1M). The acidic aqueous phase isseparated, basified with sodium hydroxide, and extracted with ethylacetate (2×100 mL). The organic layer is separated, dried (Na₂SO₄) andthe solvent removed to give an orange oil.

¹H-NMR (CDCl₃) ppm: 1.38 (s, 3H), 1.8 (br. s, 2H), 3.07 (d, 1H), 3.25(d, 1H), 3.45 (m, 2H), 7.65 (t, 1H), 7.80 (d, 1H).

2,2,2-Trifluoro-N-(2-methyl-1-oxo-indan-2-yl)-acetamide

2-Amino-2-methyl-indan-1-one (16.4 g) in THF (100 mL) is cooled to 0° C.under nitrogen. Triethylamine (21 ml) is added followed by slow additionof trifluoroacetic anhydride (18.5 ml). The reaction is stirred at roomtemperature overnight then the solvents are removed. The residue isdissolved in dichloromethane and washed with aqueous HCl followed byaqueous NaOH. The organic extract is dried (MgSO₄) and the solvent isremoved. The product is purified by chromatography (silica, ethylacetate) to give a cream solid.

¹H-NMR (CDCl₃) ppm: 1.52 (s, 3H), 3.44 (d, 1H), 3.55 (d, 1H), 7.05(br.s, 1H), 7.43 (m, 2H), 7.70 (t, 1H), 7.87 (d, 1H).

2,2,2-Trifluoro-N-(2-methyl-indan-2-yl)acetamide

2,2,2-Trifluoro-.N.-(2-methyl-1-oxo-indan-2-yl)-acetamide (3.41 g) inacetic acid (25 mL) and H₂SO₄ (0.5 mL) is stirred under hydrogen in thepresence of 10% Pd/C at room temperature for 18 hours. The mixture isfiltered through celite and the filtrate is concentrated in vacuo. Afterdiluting with water the mixture is extracted with diethyl ether. Theorganic phase is removed, washed several times with aqueous sodiumbicarbonate and dried (Na₂SO₄). The solvent is removed to give an oilwhich solidifies.

¹H-NMR (CDCl₃) ppm: 1.55 (s, 3H), 3.05 (d, 2H), 3.28 (d, 2H), 6.28(br.s, 1H), 7.12 (s, 4H).

2-Methyl-indan-2-ylamine

A stirred solution of2,2,2-trifluoro-.N.-(2-methyl-indan-2-yl)-acetamide (6.70 g) and NaOH(4.0 g) in methanol (100 mL) and water (1 mL) is heated at 70° C. for 2hours. The solvent is removed and the residue is partitioned betweenaqueous HCl (100 mL, 2M) and ethyl acetate (100 mL). The aqueous extractis separated, basified with aq. NaOH, and extracted with ethyl acetate.The organic phase is separated, dried (MgSO₄), and the solvent isremoved to give an orange oil which solidifies.

¹H-NMR (CDCl₃) ppm: 1.19 (s, 3H), 1.5 (br.s, 2H), 2.65 (d, 2H), 2.79 (d,2H), 6.97 (m, 4H).

Intermediate24-2-Methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine1-(5,6,7,8-Tetrahydro-naphthalen-2-yl)-propan-1-one

Propionyl chloride 17.5 mL) and 1,2,3,3-tetrahydronapthalene (27.5 mL)are added slowly over 1 hour to a stirred solution of AlCl₃ (61.3 g) innitromethane (200 mL) at 0° C. After stirring at room temperature for 18hours the reaction is cautiously added to a mixture of ice andconcentrated HCl. The product is extracted with ethyl acetate, washedwith brine and dried (Na₂SO₄).

¹H-NMR (CDCl₃) ppm: 1.15 (t, 3H), 1.72 (m, 4H), 2.72 (m, 4H), 2.88 (q,2H), 7.04 (d, 1H), 7.60 (m, 1H).

2-Methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-1-one

According to the procedure of Bhattacharya et. al (Synth. Commun 1996.,26, 1775-1784.) a mixture of1-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one (37.6 g),hexamethylenetetramine (44.9 g) and acetic anhydride (38.8 mL) is heatedwith stirring at 80° C. for 23 hours. The mixture is allowed to cool,and added slowly to a stirred mixture of ethyl acetate (200 mL) andaqueous sodium hydroxide (200 mL, 2M). The organic layer is separated,washed with aqueous HCl, brine, and dried (Na₂SO₄). The solvent isremoved to give a brown oil. This is added cautiously to concentratedsulfuric acid (120 mL) and the resulting mixture is heated at 55° C. for5 hours followed by room temperature for 18 hours. The reaction isdiluted with water and extracted with dichloromethane. After drying(Na₂SO₄) the solvent is removed to give an oil. The product is purifiedby chromatography (silica, ethyl acetate/hexane) to give a geometricalmixture of isomers containing2-Methyl-1,2,6,7,8,9-hexahydro-cyclopenta[.a.]naphthalen-3-one and thetitle compound.

¹H-NMR (CDCl₃) ppm (mixture): 1.4 (m, 3H), 1.9 (m, 4H), 2.5-3.0 (m, 6H),3.35 (m, 1H), 7.15 (m, 1H), 7.55 (m, 1H).

2,2,2-Trifluoro-N-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-acetamide

This compound is prepared from an isomeric mixture, containing2-methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-1-one, accordingto the procedure used for the preparation of2,2,2-trifluoro-.N.-(2-methyl-1-oxo-indan-2-yl)-acetamide. The isomericmixture of products is recrystallised from ethyl acetate/hexane to givea 4:1 mixture in favour of the title compound.

¹H-NMR (CDCl₃) ppm (major component): 1.55(s, 3H), 1.85 (m, 4H), 2.87(m, 4H), 6.88 (br.s, 1H), 7.18 (s, 1H), 7.57 (s, 1H).

TOF MS ES⁻ m/e 310 (M−H⁻)

2-Methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine

A 4:1 mixture of geometrical isomers, containing predominantly2,2,2-trifluoro-.N.-(2-methyl-1-oxo-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-acetamide,is hydrogenated over Pd/C in acetic acid/H₂SO₄ and the products aresaponified with NaOH according to the procedures described for thepreparation of 2-methyl-indan-2-ylamine. The resulting product mixtureis recrystallised repeatedly from hexane to give the title compound, asingle isomer.

¹H-NMR (CDCl₃) ppm: 1.40 (s, 3H), 1.6 (br.s, NH₂), 1.75 (m, 4H), 3.75(m, 4H), 2.78 (d, 2H), 2.94 (d, 2H), 6.93 (s, 2H).

Intermediate 25-2-Ethyl-indan-2-ylamine

2-Ethyl-indan-1-one is prepared from benzene following analogousprocedures to those used for2-methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-1-one.

¹H-NMR (CDCl₃) ppm: 0.97 (t, 3H), 1.50 (m, 1H), 1.90 (m, 1H), 2.55 (m,1H), 2.75 (dd, 1H), 3.25 (q, 1H), 7.29 (t, 1H), 7.39 (d, 1H), 7.50 (t,1H), 7.69 (d, 1H).

2-Ethyl-indan-2-ylamine is prepared from 2-ethyl-indan-1-one byprocedures analogous to those used for Intermediate 23.

¹H-NMR (CDCl₃) ppm: 1.05 (t, 3H), 1.5 (br.s, NH₂), 2.70 (q, 2H), 2.75(d, 2H), 3.01 (d,2H), 7.20 (m, 4H).

Intermediate 26-2,5,6-Trimethyl-indan-2-ylamine

2,5,6-Trimethyl-indan-2-ylamine is prepared from 1,2-dimethylbenzene byprocedures analogous to those used for2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine.

¹H-NMR (CDCl₃) ppm: 1.29 (s, 3H), 2.16 (s, 6H), 2.69 (d, 2H), 2.84 (d,2H), 2.89 (s, 2H).

Intermediate 27-Acetic acid(R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-ethylEster(R)-2-[Benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol

The title compound is prepared from(R)-2-(4-benzyloxy-3-nitro-phenyl)-oxirane (2.52 g) andbenzyl-(2-methyl-indan-2-yl)-amine (2.20 g) by an analogous procedure tothat used to prepare(S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onein Example 19. The reaction is shown to be complete by TLC after 24hours. The product is purified by flash column chromatography (silica,n-hexane/ethyl acetate 4:1).

TLC (silica, n-hexane/ethyl acetate 4:1 R_(f)=0.30).

¹H NMR [CDCl₃, 400 MHz] d 1.20 (3H, s), 2.65 (1H, m), 2.75 (1H, m), 2.90(2H, m), 3.25 (2H, m), 3.60 (1H, d), 3.70 (1H, broad), 3.80 (1H, d ofd), 4.10 (1H, d), 5.20 (2H, s), 7.00 (1H, d), 7.20 (4H, m), 7.35 (11H,m), 7.60 (1H, d).

Acetic acid(R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethylester

(R)-2-[Benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethanol(2.75 g) is dissolved in pyridine (15 mL). Acetic anhydride (1.66 g) isadded and the reaction mixture is stirred at room temperature. Thereaction is shown to be complete by TLC after 18 hours. Water (10 mL) isadded to quench the reaction. Ethyl acetate (250 mL) is added and thesolution is washed with 1M KHSO₄ (3×100 mL), saturated NaHCO₃ (10 mL),water (100 mL) and brine (100 mL). The organic layer is dried overMgSO₄, filtered and the solvent is removed in vacuo. The product is notpurified further. TLC (silica, n-hexane ethyl acetate 4:1 R_(f)=0.40).

¹H NMR [CDCl₃, 400 MHz] d 1.20 (3H, s), 1.90 (3H, s), 2.80 (3H, m), 3.00(1H, d), 3.10 (1H, m), 3.20 (1H, d), 3.75 (1H, d), 3.90 (1H, d), 5.20(2H, s), 5.25 (1H, m), 6.95 (1H, d), 7.10 (4H, m), 7.30 (11H, m), 7.55(1H, d).

Acetic Acid(R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-ethylEster

The title compound is prepared from acetic acid(R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-nitro-phenyl)-ethylester (2.90 g) by an analogous procedure to that used to prepare(R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-ethanolin Example 19. The reaction is shown to be complete by TLC after 6hours. The catalyst is filtered off and the solvent is removed in vacuo.The product is not purified further. TLC (silica; n-hexane/ethyl acetate2:1 R_(f)=0.60).

¹H NMR [CDCl₃, 400 MHz] d 1.10 (3H, s), 1.80 (3H, s), 2.70 (3H, m), 3.05(2H, m), 3.15 (1H, d), 3.65 (2H, broad), 3.75 (1H, d), 3.90 (1H, d),4.95 (2H, s), 5.20 (1H, m), 6.40 (2H, m), 6.65 (1H, d), 7.20 (14H, m).

Intermediate 28-Benzyl-(2,5,6-trimethyl-indan-2-yl)-amineN-(2,5,6-Trimethyl-indan-2-yl)-benzamide

Intermediate 26 is treated with benzoyl chloride indichloromethane/triethylamine for 1 hour. The mixture is washed with 1NHCl, then with saturated NaHCO₃ solution, dried (Na₂SO₄) and evaporated.The residue is triturated with ether/hexane to give white crystals.

¹H-NMR (CDCl₃) ppm: 1.60 (s, 3H), 2.18 (s, 6H), 3.02 (d, 2H), 3.30 (d,2H), 6.17 (br.s, NH), 6.90 (s, 2H), 7.34 (m, 2H), 7.40 (m, 1H), 7.63 (d,1H).

Benzyl(2,5,6-trimethyl-indan-2-yl)-anine

To a solution of N-(2,5,6-trimethyl-indan-2-yl)-benzamide in THF undernitrogen is added LiAlH₄ and the mixture refluxed for 48 hours. Quenchedat 0° C. with ice/water and extracted with ether, dried (Na₂SO₄) andsolvent removed in vacuo. Purification by chromatography (silica, ethylacetate/hexane 1:4) gives a colourless oil.

¹H-NMR (CDCl₃) ppm: 1.58 (s, 3H), 1.79 (br.s., NH), 2.40 (s, 6H), 3.00(d, 2H), 3.20 (d, 2H), 3.99 (s, 2H), 7.15 (s, 2H), 7.37-7.53 (m, 5H).

Intermediate 29-Acetic Acid(R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethylester(R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethanol

A mixture of 2-(4-methyl-3-nitro-phenyl)-oxirane andbenzyl-(2,5,6-trimethyl-indan-2-yl)-amine is heated at 110° C. for 48hours. The material is used without further purification.

ES⁺ MS m/e 538 (MH⁺)

Acetic Acid(R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-tri-ethyl-indan-2-yl)-amino]-ethylester

To a solution of(R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethanolin pyridine is added acetic anhydride and the mixture stirred for 18hours. The reaction mixture is quenched with water and after addition ofethyl acetate washed twice with aqueous KHSO₄ solution, twice withaqueous NaHCO₃ and once with brine. The product is purified bychromatoghaphy (silica, ethyl acetate/hexane 1:4). ES⁺ MS m/e 579 (MH⁺).

Acetic Acid(R)-1-(3-amino-4-benzyloxy-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethylester

Acetic acid(R)-1-(4-benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethylester in a mixture of THF and toluene is stirred under hydrogen in thepresence of PtO₂ at room temperature for 15 hours. The mixture isfiltered through celite and the filtrate is concentrated in vacuo. ES⁺MS m/e 549 (MH⁺).

Intermediate 30-5,6-Diethyl-2-methyl-indan-2-ylamineN-(5-Acetyl-2-thyl-indan-2-yl)-benzamide

Aluminium chloride (3.7 g) is dissolved in nitromethane (12 ml) undernitrogen followed by N-(2-methyl-indan-2-yl)-benzamide (3.0 g) at 0° C.Acetyl chloride (0.85 ml) is added dropwise over 30 minutes. After 4hours at room temperature the mixture is quenched with ice andconcentrated HCl, extracted with DCM. The organic layers are washed withdilute HCl and brine. Evaporation of the solvent yielded the desiredproduct. ES⁺ MS m/e 294 (MH⁺).

N-(5-Ethyl-2-methyl-indan-2-yl)-benzamide

A solution of N-(5-acetyl-2-methyl-indan-2-yl)-benzamide (3.4 g) inethanol (200 ml) and conc. HCl (2 ml) is stirred under hydrogen in thepresence of 10% Pd/C at room temperature for 48 hours. The mixture isfiltered through celite and the filtrate is concentrated in vacuo togive the title compound.

¹H-NMR (CDCl₃) ppm: 1.20 (t, 3H), 1.60 (s, 3H), 2.55 (q, 2H), 3.05 (d,2H), 3.35 (d, 2H), 6.35 (br.s, NH), 6.90-7.10 (m, 3H), 7.39 (d, 2H),7.65 (s, 2H)

N-(5-Acetyl-6-ethyl-2-methyl-indan-2-yl)-benzamide is prepared fromN-(5-ethyl-2-methyl-indan-2-yl)-benzamide (2.6 g) following theprocedure used to prepare N-(5-acetyl-2-methyl-indan-2-yl)-benzamide.The product is purified by chromatography (silica, hexane ethyl acetate,4:1) to give the title compound. ES⁺ MS m/e 322 (MH⁺).

N-(5,6-Diethyl-2-methyl-indan-2-yl)-benzamide is prepared fromN-(5-acetyl-6-ethyl-2-methyl-indan-2-yl)-benzamide (1.1 g) following theprocedure used to prepare N-(5-ethyl-2-methyl-indan-2-yl)-benzamide. ES⁺MS m/e 308 (MH⁺).

Benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine is prepared fromN-(5,6-diethyl-2-methyl-indan-2-yl)-benzamide by an analogous procedureto that used to prepare benzyl-(5,6-diethyl-indan-2-yl)-amine inIntermediate 18. ES⁺ MS m/e 294 (MH⁺).

5,6-Diethyl-2-methyl-indan-2-ylamine

A solution of benzyl-(5,6-diethyl-2-methyl-indan-2-yl)-amine (0.48 g) inmethanol (10 ml) is stirred under an atmosphere of hydrogen in thepresence of 10% Pd/C at room temperature for 18 hours. The mixture isfiltered through celite and the filtrate is concentrated in vacuo togive the title compound. ES⁺ MS m/e 204 (MH⁺)

EXAMPLE 1(R)-8-Benzyloxy-5-[2-(4,7-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one

(R)-8-Benzyloxy-5-oxiranylcarbostyril (100 mg, 0.34 mmol), prepared fromliterature procedure (Beeley, Lee James; Dean, David Kenneth, PCT Int.Appl. WO 9525104) and 4,7-dimethoxy-indan-2-ylamine (66 mg, 0.34 mmol),prepared from literature procedure (Sindelar, R. D.; Mott, J.;Barfknecht, C. F.; Arneric, S. P.; Flynn, J. R.; Long, J. P.; Bhatnagar,R. K. J. Med. Chem. (1982), 25(7), 858-64), are dissolved in toluene (1mL). The reaction mixture was heated to 110° C. and the solvent isallowed to evaporate. The residue is then stirred at 110° C. for 4hours. The reaction is shown to be complete by TLC. The product ispurified by flash column chromatography (silica, dichloromethanemethanol 20:1).

TLC (silica, dichloromethane/methanol 25:1 R_(f)=0.10).

ES+ MS m/e 487 (MH⁺).

(R)-8-hydroxy5-[2-(4,7-Dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onehydrochloride

(R)-8-hydroxy5-Benzyloxy-5-[2-(4,7-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one(37 mg, 0.08 mmol) is dissolved in methanol (10 mL) and the compound isdeprotected by adding a catalytic amount of 10% palladium on charcoaland placing the solution under an atmosphere of hydrogen. The reactionis shown to be complete by TLC after 4 hours. The catalyst is filteredoff, 1M HCl/diethyl ether (1.1 equivalent) is added and the solvent isremoved in vacuo.

TLC (silica, dichloromethane/methanol 10:1 R_(f)=0.15).

ES+ MS m/e 397 (MH⁺).

Other compounds of formula I are prepared from(R)-8-benzyloxy-5-oxiranylcarbostyril((R)-2-(4-benzyloxy-3-nitrophenyl)-oxirane (Intermediate 15) in Example11) and the appropriate compound of formula XVII by procedures analogousto Example 1. These compounds, in which R¹ is OH, R² and R³ are H, Ar isa group of formula m in which R²⁹, R³⁰ and R³¹ are H (except in Example11, where Ar is a group of formula XV in which R¹³ is H) and n is 1(except in Example 9 where n is 2) are shown in the following table.

Example R⁴ R⁵ R⁶ R⁷ ES + MS m/e (MH⁺) 2 H CH₃CH₂ CH₃CH₂ H 393 3 H CH₃CH₃ H 365 4 CH₃CH₂ H H CH₃CH₂ 393 5 H —(CH₂)₄— H 391 6 H —O(CH₂)₂O— H395 7 H CH₃(CH₂)₃ CH₃(CH₂)₃ H 449 8 H CH₃(CH₂)₂ CH₃(CH₂)₂ H 421 9 H H HH 365 10  H CH₃OCH₂ CH₃OCH₂ H 11  H CH₃CH₂ CH₃CH₂ H 341

EXAMPLE 10

¹H-NMR (d₄-MeOH) ppm: 2.78 (2H, m), 2.9 (2H, m), 3.15 (2H, m), 3.28 (6H,s), 3.7 (1H, m), 4.55 (1H, br s), 5.15 (1H, m), 6.58 (1H, d), 6.9 (1H,d), 7.11 (2H, s), 7.15 (1H, s), 8.25 (1H, s).

EXAMPLE 128-Hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-one

Intermediate 10 (18 mg, 0.054 mmol) is dissolved in methanol (2 mL) andcooled on ice. Sodium borohydride (6 mg, 0.12 mmol) is added over 2hours. Concentrated HCl is then added until pH reaches 1, and thereaction mixture filtered. The filtrate is washed with methanol. Thecombined liquid phases are evaporated and redisolved in methanol twice.After removal of the methanol in vacuo, the residue is redisolved inwater and the pH brought to 12 with 1N KOH. The solvent is removed invacuo and the residue coevaporated twice with toluene. The residue ispurified by flash chromatography (silica, CH₂Cl₂/methanol 8:2). ES+ MSm/e 337 (MH+).

EXAMPLE 135-[2-(5,6-Dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one

This compound is prepared from Intermediate 11 by a procedure analogousto that of Example 12. ES+MS m/e 397 (MH⁺)

EXAMPLE 145-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-quinolin-2-one

This is prepared from Intermediate 13 (21 mg) by the hydrogenationprocedure for removal of the benzyl group used in Example 1.

¹H-NMR (d4-CH₃OH) ppm 1.11 (t, 6H), 2.11 (s, 3H), 2.58 (q, 4H),3.01-3.37 (m, 6H), 4.10-4.16 (m, 1H), 5.31-5.38 (m, 1H), 6.91 (d, 1H),7.00 (s, 2H), 7.21 (d, 1H), 8.13 (s, 1H).

EXAMPLE 155-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-1H-quinolin-2-one

This is obtained from Intermediate 14 (20 mg) and5,6-diethyl-indan-2-ylamine (72 mg) according to the procedure used forpreparation of Intermediate 13.

¹H-NMR (CDCl₃) ppm: 1.14 (t, 6H), 2.30 (s, 3H), 2.51 (q, 4H), 2.64-3.16(m, 6H), 3.41 (s, 3H), 3.60-3.68 (m, 1H), 5.18-5.25 (m, 3H), 6.50 (d,1H), 7.89-7.94 (m, 3H), 8.68 (d, 2H), 9.15 (s, br, 1H).

5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-one

3N Hydrochloric acid (1 mL) is added to a solution of5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-1H-quinolin-2-one(12 mg) in isopropanol (1 mL) and tetrahydrofuran (1 mL) at roomtemperature and the reaction mixture heated for 18 hours at 40° C. Thesolvent is removed in vacuo, and the product purified by preparativescale HPLC on a C8 column, eluting with awater/acetonitrile/trifluoroacetic acid gradient.

¹³C-NMR (d4-CH₃OH) ppm: 15.97, 20.09, 26.34, 36.87, 51.75, 59.72, 67.33,118.41, 119.12, 121.21, 125.45, 126.11, 128.60, 133.35, 137.52, 137.55,142.32, 142.50, 145.69, 163.24.

EXAMPLE 168-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-quinolin-2-one

Hydrogenation of a methanol/ethanol solution of8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one(Example 2) with a 10% palladium on carbon catalyst at 30° C. for 48hours under one atmosphere of hydrogen gives the title compound afterfiltration and evaporation. Further purification is achieved viapreparative HPLC (column: Phenomenex Luna 10 μm 150 mm×50 mm, eluent:gradient from 10% to 95% acetonitrile in water containing 0.1%trifluoroacetic acid, UV detection at 254 nm).

¹³C-NMR (d6-DMSO) ppm: 15.77, 21.42, 25.01, 30.37, 37.73, 37.83, 53.88,58.68, 67.37, 113.28, 120.21, 122.08, 124.31, 124.34, 131.01, 138.46,138.52, 139.58, 143.12, 169.44.

EXAMPLE 17 (a) Acetic Acid(R)-1-(4-benzyloxy-3-formylamino-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethylEster

To Intermediate 29 in toluene/THF is slowly added an aged mixture offormic acid and acetic anhydride and the reaction is stirred for 5 hoursat room temperature. Ethyl acetate is added and washed with saturatedNaHCO₃ solution. Purification by chromatography (silica, ethylacetate/hexane 1:2) and trituration with ether gave off-white crystals.ES⁺ MS m/e 577 (MH⁺).

(b)N-(2-Benzyloxy-5-{(R)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-phenyl)-formamide

The product of Example 17(a) is suspended in ethanol and a catalyicamount of NaOCH₃ in methanol is added. After two hours at 70° C. thesolvent is removed and the residue purified by chromatography (silica,ethyl acetate hexane 2:3) to give white crystals. ES⁺ MS m/e 535 (MH⁺).

(c)N-{2-Hydroxy-5-[(R)-1-hydroxy-2-(2,5,6-trimethyl-indan-2-ylamino)-ethyl]-phenyl}-formamideis prepared from the product of example 17(b) by a procedure analogousto that of Example 34(c). ES⁺ MS m/e 355 (MH⁺)

EXAMPLE 18 (a)8-Benzylamino-5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one

A mixture of 5,6-diethyl-2-methyl-indan-2-ylamine (0.28 g) and8-benzyloxy-5-oxiranyl-1H-quinolin-2-one (0.42 g) in n-butanol (0.7 ml)is placed in a Prolabo microwave oven for 75 minutes. at 100° C. Theproduct is purified by chromatography (silica, DCM/ethanol, 5:1) to givethe desired product. ES⁺ MS m/e 497 (MH⁺).

5-[(R)-2-(5,6-Diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one

A solution of the product of Example 18(a) (0.20 g) in methanol (20 ml)is stirred under an atmosphere of hydrogen in the presence of 10% Pd/Cat room temperature for 2 hours. The mixture is filtered through celiteand the filtrate is concentrated in vacuo. Trituration with diethylether gave the desired product. ES⁺ MS m/e 407 (MH⁺).

EXAMPLE 19

(a)(S)-8-Benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-oneis prepared from Intermediate 16 (152 mg) and Intermediate 1 (100 mg)using a procedure analogous to that of Example 1(a). TLC (silica,dichloromethane/methanol 10:1 R_(f)=0.25).

(b)(S)-5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride is prepared from the product of Example 19(a) by aprocedure analogous to that of Example 1(b). TLC (silica,dichloromethane/methanol 10:1 R_(f)=0.05).

EXAMPLE 20

(a)8-Benzyloxy-5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-1H-quinolin-2-oneis prepared from (R)-8-benzyloxy-5-oxiranylcarbostyril (203 mg) andIntermediate 17 (110 mg) by a procedure analogous to that of Example1(a). TLC (silica, dichloromethane methanol 10:1 R_(f)=0.30).

(b)S-[(R)-1-Hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-onehydrochloride is prepared from the product of Example 20(a) by aprocedure analogous to that of Example 1(b). TLC (silica,dichloromethane/methanol 10:1 R_(f)=0.05).

EXAMPLE 21 (a)(R)-8-benzyloxy-5-{(S)-2-[benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-1H-quinolin-2-one

A solution of (R)-8-benzyloxy-5-oxiranylcarbostyril (5.00 g) and2-amino-5,6-diethylindan (3.87 g) in n-butanol is heated for 4 hours at110° C. After cooling to room temperature toluene (100 ml) is added andthe organic phase is washed with water (3×25 ml), loaded onto a silicagel chromatography column and eluted with toluene followed by a mixtureof toluene:ethanol:ethyl acetate:conc. ammonia (45:10:45:2) to give thetitle compound.

(b)(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate(R)-8-benzyloxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-one(360 mg) is dissolved in methanol (10 mL) and the compound isdeprotected by adding a catalytic amount of 10% palladium on charcoaland placing the solution under an atmosphere of hydrogen. The reactionis shown to be complete by TLC after 4 hours. The catalyst is filteredoff and the solvent is removed in vacuo. The product is taken up intoisopropanol and a solution of maleic acid in isopropanol added. Thetitle compound is obtained after recrystallisation from ethanol. TLC(silica, dichloromethane/methanol 10:1 R_(f)=0.05). E5+ MS m/e 393(MH⁺).

EXAMPLE 22

(a)N-(5-{(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-2-benzyloxyphenyl)-formamideis prepared from Intermediate 19 (1.00 g), formic acid (155 mg) andacetic anhydride (226 mg) using a procedure analogous to that of Example21(a). TLC (silica, n-hexane/ethyl acetate 2:1 R_(f)=0.20).

(b)N-{5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-formamideis prepared from the product of Example 22(a) by a procedure analogousto that of Example 1(b). TLC (silica, n-hexane ethyl acetate 2:1R_(f)=0.05).

EXAMPLE 23 (a)(R)-2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-dimethylamino-phenyl)-ethanol

Intermediate 19 (0.37 g) is dissolved in CH₃OH (50 mL) and formaldehyde,37% in water (5 mL), dissolved in water (10 mL), is added. A catalyticamount of PtO₂ is added and the solution is stirred under an atmosphereof H₂. The reaction is shown to be complete by TLC after 24 hours. Thecatalyst is filtered off, the solvent is removed in vacuo and theresidue is partitioned between ethyl acetate (100 mL) and water (100mL). The organic layer is dried over MgSO₄, filtered and the solvent isremoved in vacuo. The product is purified by flash column chromatography(silica, n-hexane/ethyl acetate 4:1). TLC (silica,n-hexane/ethyl-acetate 2:1 R_(f)=0.65).

(b)4-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-2-dimethylamino-phenolhydrochloride is prepared from the product of Example 23(a) by aprocedure analogous to that of Example 1(b).

¹H NMR [DMSO, 400 MHz] δ 1.10(6H,t), 2.55 (4H, q), 3.05(2H,m), 3.10 (6H,s), 3.20 (4H, m), 4.00 (1H, m), 4.95 (1H, m), 7.00 (2H, s), 7.15 (1H,d), 7.35 (1H, d), 7.80 (1H, s), 9.20 (1H, broad), 9.75 (1H, broad),11.40 (1H, broad).

EXAMPLE 24 (a)(R)-2-[Benzyl-(5,6-diethylindan-2-yl)-amino]-1-(4-benzyloxy-3-methylamino-phenyl)-ethanol

The product of Example 22 (260 mg) is dissolved in dioxan (20 mL).Sodium borohydride (90 mg) is added followed by the dropwise addition ofacetic anhydride (142 mg). The reaction mixture is stirred at 90° C. Thereaction is shown to be complete by TLC after 4 hours. The solvent isremoved in vacuo and the residue is partitioned between ethyl acetate(100 mL) and water (10 mL). The organic layer is dried over MgSO₄,filtered and the solvent is removed in vacuo. The product is purified byflash column chromatography (silica, n-hexane/ethyl acetate 4:1). TLC(silica, n-hexane/ethyl acetate 2:1 R_(f)=0.65).

(b)4-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-2-methylamino-phenolhydrochloride is prepared from the product of Example 24(a) by aprocedure analogous to that of Example 1 (b).

¹H NMR [DMSO, 400 MHz] δ 1.10(6H,t), 2.55 (4H, q), 2.85 (3H, s), 3.10(6H, m), 4.00 (1H, m), 4.90 (1H, m), 7.00 (3H, m), 7.15 (1H, m), 7.40(1H, m), 9.10 (1H, broad), 9.60 (1H, broad), 10.80 (1H, broad).

EXAMPLE 25 (a)N-(5-{[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-acetyl}2-benzyloxy-phenyl)-methanesulfonamide

Intermediate 20 (240 mg) is dissolved in dichloromethane (10 mL).Triethylamine (56 mg) is added followed by methanesulfonyl chloride (58mg). The reaction mixture is stirred at room temperature. The reactionis shown to be complete by TLC after 24 hours. The solvent is removed invacuo and the product is purified by flash column chromatography(silica, n-hexane/ethyl acetate 4:1). TLC (silica, n-hexane/ethylacetate 2:1 R_(f)=0.40).

(b)N-(5-{2-[Benzyl-(5,6-diethyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-2-benzyloxy-phenyl)-methanesulfonamide

The product of Example 25(a) (120 mg) is dissolved in ethanol (10 mL).Sodium borohydride (9 mg) is added and the reaction mixture is stirredat room temperature. The reaction is shown to be complete by TLC after 3hours. The reaction mixture is quenched with 2M HCl (1 mL), the solventis removed in vacuo and the residue is partitioned between ethyl acetate(50 mL) and saturated NaHCO₃ (50 mL). The organic layer is dried overMgSO₄, filtered and the solvent is removed in vacuo. The product is notpurified further. TLC (silica, n-hexane/ethyl acetate 2:1 R_(f)=0.45).

(c)N-{5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamidehydrochloride) is prepared from the product of Example 25(b) by aprocedure analogous to that of Example 1 (b).

¹H NMR [CDCl₃, 400 MHz] δ 1.15(6H,t), 2.55 (4H, q) 2.95 (3H,s), 3.10(6H,m), 4.00 (1H, m), 4.85 (1H, m), 6.10 (1H, broad), 6.90 (2H, d), 7.00(2H, s), 7.10 (1H, d of d), 7.25 (1H, d), 8.75 (1H, s), 8.95 (1H,broad), 9.25 (1H, broad), 10.00 (1H, s).

EXAMPLE 26 (a)(R)-8-Benzyloxy-5-{(S)-2-[benzyl-(4,5,6,7-tetramethyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-1H-quinolin-2-one

(R)-8-Benzyloxy-5-oxiranylcarbostyril (204 mg) and Intermediate 21 (194mg) are dissolved in n-butanol (0.5 ml) under nitrogen. The reactionmixture is heated at 110° C. for 22 hours. On cooling the solvent isremoved in vacuo. The product is purified by flash column chromatography(silica, ethyl acetate/heaxane 50:50). ES⁺ MS m/e 573 (MH⁺).

(b)(R)-8-Hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-oneis prepared from the product of Example 26(a) by a procedure analogousto that of Example 1(b).

¹H NMR (CD₃OD) ppm: 8.55 (1H, d); 7.5 (1H, d); 7.25 (1H, d); 6.9 (1H,d); 5.6 (1H, m); 4.3 (1H, m); 3.7 (2H, q); 3.6 (2H, dd); 3.3 (2H, dd);2.4 (12H, s)

EXAMPLE 27 (a)8-Benzyloxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-one

A mixture of 8-benzyloxy-5-(R)-oxiranyl-1H-quinolin-2-one (500 mg) and2-methyl-indan-2-ylamine (276 mg) in n-butanol (1 mL) is subjected tomicrowave irradiation, using a Prolabo Synthewave 402 instrument, for 90minutes at 110° C. The residue is absorbed on silica and the product ispurified by flash chromatography (silica, chloroform/ethanol 4:1).

¹H-NMR (CDCl₃) ppm: 1.30 (s, 3H), 2.65 (s, 1H), 2.95 (dd, 2H), 3.07 (m,3H), 5.15 (m, 1H), 5.18 (s, 2H), 6.66 (d, 1H), 7.17 (m, 4H), 7.26 (d,1H), 7.45 (m, 5H), 8.07 (d, 1H), 8.8-9.5 (br.d, 1H)

(b)8-Hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin-2-one

The product of Example 27(a) (100 mg, 0.22 mmol) is dissolved inmethanol (20 mL) and is deprotected by adding a catalytic amount of 10%palladium on charcoal and stirring under an atmosphere of hydrogen for 1hour. The catalyst is removed and the solvent is evaporated to give ayellow solid.

¹H-NMR (d4-CH₃OH) ppm: 1.20 (s, 3H), 2.75 (m, 4H), 2.95 (d, 2H), 5.03(m, 1H), 6.60 (d, 1H), 6.82 (d, 1H), 7.0 (m, 4H), 7.08 (d, 1H), 8.20 (d,1H).

EXAMPLE 285-[2-(5,6-Diethylindan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-one

This compound is prepared from the product of Example 2 according to theprocedure of Temple et al, J. Med. Chem., 19, 626-633 (1976).

¹H-NMR (d₄-CH₃OH) ppm: 1.08 (t, 3H), 2.55 (q, 4H), 2.96 (dd, 2H), 3.18(m, 4H), 3.28 (dd, 2H), 3.99 (m, 1H), 6.60 (d, 1H), 6.90 (d, 1H), 6.97(d, 1H), 6.00 (s, 2H), 8.07 (d, 1H).

EXAMPLE 29

(a)8-Benzyloxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta-[b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-oneis prepared from 8-benzyloxy-5-(R)-oxiranyl-1H-quinolin-2-one (220 mg)and Intermediate 24 (150 mg) by procedures analogous to those of Example27(a).

¹H-NMR (CDCl₃) ppm: 1.37 (s, 1H), 1.78 (m, 4H), 2.1 (br.s, 2H), 2.72 (m,5H), 2.80 (dd, 2H), 2.95 (m, 3H), 5.08 (m, 1H), 5.17 (s, 2H), 6.65 (d,1H), 6.88 (s, 2H), 7.02 (d, 2H), 7.26 (d, 1H), 7.4 (m, 5H), 8.05 (d,1H).

(b)8-Hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta-[b]naphthalen-2-ylamino)ethyl]-1H-quinolin-2-oneis prepared by hydrogenation of the product of Example 29(a) using aprocedure analogous to that of Example 27(b). The product is purified byHPLC (H₂O, CH₃CN, CF₃COOH, gradient elution).

¹H-NMR (d₄-CH₃OH) ppm (TFA salt): 1.65 (s, 3H), 1.85 (m, 4H), 2.85 (m,4H), 3.15 (m, 2H), 3.4 (m, 4H), 5.48 (t, 1H), 6.83 (d, 1H), 7.03 (s,2H), 7.15 (d, 1H), 7.45 (d, 1H), 8.40 (d, 1H).

EXAMPLE 30 (a) 5-{(S)-2-[Benzyl-(2,3,5,6,7,8-hexahydro-1Hcyclopenta[b]naphthalen-2-yl)-amino]-1-hydroxy-ethyl}-8-benzyloxy-1H-quinolin-2-one

A mixture of Intermediate 16 (150 mg) andbenzyl-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-yl)-amine(142 mg) in toluene (1 mL) is heated at 80° C. for 36 hours. The residueis purified by chromatography (silica, CHCl₃/EtOH, 20:1) to give ayellow foam.

¹H-NMR (CDCl₃) ppm: 1.77 (m, 4H), 2.72 (m, 6H), 3.01 (m, 4H), 3.70 (d,1H), 3.88 (d, 1H), 4.82 (m, 1H), 5.15 (s, 2H), 6.50 (d, 1H), 6.8-8 (m,13H), 9.05 (br.s, 1H)

(b)5-[(S)-2-(2,3,5,6,7,8-Hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one

A solution of the product of Example 30(a) (150 mg) in methanol (20 mL)is stirred under an atmosphere of hydrogen in the presence of 10% Pd/C(20 mg) at room temperature for 5 hours. The rection is filtered and theproduct is purified by chromatography (silica, CHCl₃/EtOH, 20:1)followed by crystallisation (CH₃OH).

¹H-NMR (d₄-CH₃OH) ppm: 1.65 (m, 4H), 2.57 (m, 4H), 2.86 (dd, 2H), 3.1(m, 4H), 3.82 (m, 1H), 5.25 (m, 1H), 6.55 (d, 1H), 6.78 (s, 2H), 6.91(d, 11H), 7.19 (d, 1H), 8.27 (d, 1H).

EXAMPLE 31

(a) Acetic acid(R)-2-[benzyl(2-methyl-indan-2-yl)amino]-1-(4-benzyloxy-3-methanesulfonylamino-phenyl)-ethylester is prepared from Intermediate 27 (476 mg), triethylamine (231 mg)and methanesulfonyl chloride (210 mg) by a procedure analogous to thatof Example 25(b). TLC (silica, n-hexane/ethyl acetate 2:1 R_(f)=0.45).

(b)N-(5-{(R)-2-[Benzyl-(2-methyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-2-benzyloxy-phenyl)-methanesulfonamide

The product of Example 31(a) (200 mg) is dissolved in CH₃OH (8 mL).K₂CO₃ (138 mg) is added followed by the dropwise addition of water (2mL). The reaction mixture is stirred at room temperature. The reactionis shown to be complete by TLC after 24 hours. Ethyl acetate (100 mL) isadded and the solution is washed with water (50 mL) and brine (50 mL).The organic layer is dried over MgSO₄, filtered and the solvent isremoved in vacuo. The product is purified by flash column chromatography(silica, n-hexane/ethyl acetate 3:1). TLC (silica, n-hexane/ethylacetate 2:1 R_(f)=0.35).

(c)N-{2-Hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-phenyl}-methanesulfonamide)is prepared from the product of Example 31(b) by a procedure analogousto that of Example 1(b). TLC (silica, dichloromethane/methanol 10:1R_(f)=0.10).

EXAMPLE 32

(a) Acetic acid(R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-(4-benzyloxy-3-ethanesulfonylamino-phenyl)-ethylester is prepared from Intermediate 27, triethylamine (242 mg) andethanesulfonyl chloride (247 mg) by a procedure analogous to that ofExample 25(b). TLC (silica, n-hexane ethyl acetate 2:1 R_(f)=0.50).

(b) Ethanesulfonic acid(5-{(R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-2-benzyloxy-phenyl)-amideis prepared from the product of Example 32(a) by a procedure analogousto that in Example 31(b). TLC (silica, n-hexane ethyl acetate 2:1R_(f)=0.40).

(c) Ethanesulfonic acid{2-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-phenyl}-amideis prepared from the product of Example 32(b) by a procedure analogousto that of Example 1(b). TLC (silica, dichloromethane/methanol 10:1R_(f)=0.10).

EXAMPLE 33

(a) Acetic acid (R)-2-[benzyl(2-methyl-indan-2-yl)-amino]-1-[4-benzyloxy-3-(propane-1-sulfonylamino)-phenyl]-ethylester) is prepared from Intermediate 27 (525 mg), triethylamine (255 mg)and 1-propanesulfonyl chloride (288 mg) by a procedure analogous to thatof Example 25 (a). TIC (silica, n-hexane/ethyl acetate 4:1 R_(f)=0.25).

(b) Propane-1-sulfonic acid(5-{(R)-2-[benzyl-(2-methyl-indan-2-yl)-amino]-1-hydroxy-ethyl}-2-benzyloxy-phenyl)-amideis prepared from the product of Example 33(a) by a procedure analogousto of Example 31(b). TLC (silica, n-hexane/ethyl acetate 4:1R_(f)=0.15).

(c) Propane-1-sulfonic acid{2-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-phenyl}-amideis prepared from the product of Example 33(b) by a procedure analogousto that of Example 1(b). TLC (silica, dichloromethane/methanol 10:1R_(f)=0.05).

EXAMPLE 34 (a)N-{2-Benzyloxy-5-[(2-ethyl-indan-2-ylamino)-acetyl]-phenyl}-methanesulfonamide

A mixture of 2-ethyl-indan-2-ylamine andN-(2-benzyloxy-5-bromoacetyl-phenyl)-methanesulfonamide is stirred inacetonitrile at room temperature for 20 hours. The product is isolatedby filtration. ES⁺ MS m/e 479 (MH⁺).

(b)N-{2-Benzyloxy-5-[2-(2-ethyl-indan-2-ylamino)-1-hydroxy-ethyl]-phenyl}-methanesulfonamide

The product of Example 34(a) is suspended in a mixture of ethanol anddichloromethane. Sodium borohydride is added at 0° C. and the mixturestirred at room temperature for 3 hours, then filtered andchromatographed (silica, ethylacetate/ethanol 4:1) to give a white foam.ES⁺ MS m/e 480 (MH⁺).

(c)N-{5-[2-(2-Ethyl-indan-2-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamide

The product of Example 34(b) (0.29 g) in methanol (20 mL) is stirredunder hydrogen in the presence of 10% Pd/C at room temperature for 18hours. The mixture is filtered through celite and the filtrate isconcentrated in vacuo, then chromatographed (silica, ethylacetate/ethanol 2:1). After trituration with ether/ethyl acetateoff-white crystals (100 mg) are obtained.

¹H-NMR (d₄-CH₃OH) ppm: 0.85 (t, 3H), 1.65 (m, 2H), 2.75 (m, 2H), 2.85(s, 3H), 2.95 (m, 4H), 6.80 (d, 1H), 7.05 (m, 5H), 7.30 (s,1H).

ES⁺ MS m/e 491 (MH⁺)

EXAMPLE 35 (a) Acetic Acid(R)-1-(4-benzyloxy-3-methanesulfonylamino-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethyl ester

To a solution of Intermediate 29 in dichloromethane and triethylamine atroom temperature is added methanesulfonyl chloride and the mixturestirred for 18 hours. It is then washed with 0.2 N HCl, saturated NaHCO₃solution and brine. The product is purified by chromatogaphy (silica,ethyl acetate I hexane 1:4). ES⁻ MS m/e 625 (M⁻).

(b)N-(2-Benzyloxy-5-{(R)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-1-hydroxyethyl}-phenyl)-methanesulfonamide

The product of Example 35(a) is stirred in methanol/water with K₂CO₃ for3 days then solvents removed in vacuo. The product is purified bychromatography (silica, ethyl acetate/hexane 1:2).

¹H-NMR (CDCl₃) ppm: 1.21 (s, 3H), 2.22 (s, 6H), 2.63-2.82 (m, 4H), 2.84(s, 3H), 3.20 (br.d, 2H), 3.61 (d,1H), 3.64 (br.s., 1H), 3.83 (m, 1H),4.08 (d, 1H), 5.09 (s, 2H), 6.75 (br.s, NH), 6.90-7.05 (m, 4H),7.25-7.45 (11H).

(c)N-{2-Hydroxy-5-[(R)-1-hydroxy-2-(2,5,6-trimethyl-indan-2-ylamino)-ethyl]-phenyl}-methanesulfonamideis prepared from the product of Example 35(b) by a procedure analogousto that of Example 34(c). ES⁺ MS m/e 405 (MH⁺).

1. A combination comprising: (a)(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,in free or salt or solvate form; and (b) a steroid.
 2. The combinationof claim 1 wherein the steroid is selected from the group consisting ofbudesonide, beclamethosone, fluticasone and mometasone.
 3. Thecombination of claim 1 wherein (a) is(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate.
 4. The combination of claim 1 wherein (b) is mometasone.
 5. Thecombination of claim 1 wherein (a) is(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one maleate and (b) is mometasone.
 6. A pharmaceuticalcomposition comprising a combination of claim 1 and a pharmaceuticallyacceptable carrier.
 7. A method of treating a patient with anobstructive or inflammatory airways disease comprising administering tothe patient in need of such treatment a therapeutically effective amountof the combination of claim 1.